Publications

There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos.

At present cancer genetics referrals are reactive to individuals asking for a referral and providing a family history thereafter. A previous pilot study in a single General Practice (GP) catchment area in North London showed a 1.5-fold increase in breast cancer risk in the Ashkenazi Jewish population compared with the non-Ashkenazi mixed population. The breast cancer incidence was equal in the Ashkenazim in both pre- and postmenopausal groups. We wanted to investigate the effect of proactively seeking family history data from the entire female population of the practice to determine the effect on cancer genetics referral. Objectives To determine the need for cancer genetics intervention for women in a single GP catchment area. (1) to determine the incidence and strength of family history of cancer in women aged over 18 in the practice, (2) to offer cancer genetics advice and determine the uptake of counselling in those with a positive family history, (3) to identify potential BRCA1/BRCA2 gene mutation carriers who can be offered clinical follow up with appropriate translational research studies. Design Population-based cohort study of one General Practice female population. Participants Three hundred and eighty-three women over the age of 18 from one General Practice who responded to a questionnaire about family history of cancer. The whole female adult GP population was the target and the total number sampled was 3,820. Results 10% of patients completed the questionnaire (n = 383). A family history of cancer was present in 338 cases, 95 went on to have genetic counselling or had previously had counselling and 47 were genetically tested. We identified three carriers of an Ashkenazi Jewish founder mutation in BRCA1. Conclusions Response rate to a family history questionnaire such as that used in genetics centres was low (10%) and other approaches will be needed to proactively assess family history. Although the Ashkenazim are present in 39% of the GP catchment area, 62% of those who returned a family history questionnaire were from this ethnic group and of those returned, 44% warranted referral to a cancer genetics unit. In the non Ashkenazim, the questionnaire return rate was 38% and 18% of those warranted referral to cancer genetics.

Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs.

Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction.

Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set.

One of the strongest risk factors for prostate cancer is a family history of the disease. Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men ≤65 years). Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease. As we present here, BRCA germline mutations, mainly in the BRCA2 gene, are one of those predictive factors. We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics.

Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures.

Prostate-specific antigen is currently commonly used as a screening biomarker for prostate cancer, but it has limitations in both sensitivity and specificity. The development of novel biomarkers for early cancer detection has the potential to improve survival, reduce unnecessary investigations and benefit the health economy. Here we review the use and limitations of prostate-specific antigen and its subtypes, urinary biomarkers including PCA3, alpha-methylacyl-CoA racemase, the TMPRSS2-ERG fusion gene and microseminoprotein-beta, and other novel markers in both serum and urine. Many of these biomarkers are at early stages of development and require evaluation in prospective trials to determine their potential usefulness in clinical practice. Genetic profiling may allow for the targeting of high-risk populations for screening and may offer the opportunity to combine biomarker results with genotype to aid risk assessment.

We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.

It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines.

What's known on the subject? and What does the study add? The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Over the last 5 years, genome-wide association studies (GWAS) have reported numerous susceptibility loci that predispose individuals to many different traits. The present study aims to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention. OBJECTIVES: •  To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa). •  To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA). MATERIALS AND METHODS: •  The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls. •  In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS. •  Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni). RESULTS: •  In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12. •  After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P= 6 × 10(-4) ; odds ratio [OR]= 1.15, 95% CI: 1.06-1.24); this has also been associated with psoriasis. •  However, further analyses showed that the association of this allele was due to confounding by RA-associated HLA-DRB1 alleles. CONCLUSIONS: •  There is currently no evidence that SNPs associated with PrCa at genome-wide significance are associated with the development of RA. •  Studies like this are important in determining if common genetic risk profiles might predispose individuals to many diseases, which could have implications for public health in terms of screening and chemoprevention.

To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported.

The ratio of digit lengths is fixed in utero, and may be a proxy indicator for prenatal testosterone levels.

Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

Compelling evidence supports a genetic component to prostate cancer susceptibility and aggressiveness. Recent genome-wide association studies have identified more than 30 single-nucleotide polymorphisms associated with prostate cancer susceptibility. It remains unclear, however, whether such genetic variants are associated with disease aggressiveness--one of the most important questions in prostate cancer research today. To help clarify this and substantially expand research in the genetic determinants of prostate cancer aggressiveness, the first National Cancer Institute Prostate Cancer Genetics Workshop assembled researchers to develop plans for a large new research consortium and patient cohort. The workshop reviewed the prior work in this area and addressed the practical issues in planning future studies. With new DNA sequencing technology, the potential application of sequencing information to patient care is emerging. The workshop, therefore, included state-of-the-art presentations by experts on new genotyping technologies, including sequencing and associated bioinformatics issues, which are just beginning to be applied to cancer genetics.

The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. We sought to elucidate the role of common genetic variation in four of the Kallikrein genes, KLK5, KLK6, KLK12, and KLK13, in prostate cancer risk and tumor aggressiveness. Genotyping of all 22 tagging single nucleotide polymorphisms (tagSNPs) in the KLK5, KLK6, KLK12, and KLK13 genes was performed in approximately 1,000 prostate cancer cases and 1,300 male controls from Australia. Data from any positive results were also accessed for 1,844 cases and 1,886 controls from a previously published prostate cancer genome-wide association study set from the United Kingdom. For one SNP in KLK12, rs3865443, there was evidence for association with prostate cancer risk of similar direction and magnitude in the replication set to that seen in the Australian cohort. We conducted genotyping of a further 309 prostate cancer cases, and combined analyses revealed an increased risk of prostate cancer for carriers of the rare homozygous genotype for rs3865443 (OR 1.28, 95% CI 1.04-1.57; P = 0.018). No other tagSNPs in the KLK5, KLK6, and KLK13 genes were consistently associated with prostate cancer risk or tumor aggressiveness. Analysis of a combined sample of 3,153 cases and 3,199 controls revealed the KLK12 tagSNP rs3865443 to be marginally statistically significantly associated with risk of prostate cancer. Considering the total number of SNPs investigated in this study, this finding should be interpreted cautiously and requires additional validation from very large datasets such as those of the Prostate Cancer Association group to investigate cancer associated alterations (PRACTICAL) Consortium.

Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ∼25% of the familial risk in this disease, have now been identified.

Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) that are independently associated with small increments in risk of prostate cancer, opening up the possibility for using such variants in risk prediction. Using segregation analysis of population-based samples of 4,390 families of prostate cancer patients from the UK and Australia, and assuming all familial aggregation has genetic causes, we previously found that the best model for the genetic susceptibility to prostate cancer was a mixed model of inheritance that included both a recessive major gene component and a polygenic component (P) that represents the effect of a large number of genetic variants each of small effect, where . Based on published studies of 26 SNPs that are currently known to be associated with prostate cancer, we have extended our model to incorporate these SNPs by decomposing the polygenic component into two parts: a polygenic component due to the known susceptibility SNPs, , and the residual polygenic component due to the postulated but as yet unknown genetic variants, . The resulting algorithm can be used for predicting the probability of developing prostate cancer in the future based on both SNP profiles and explicit family history information. This approach can be applied to other diseases for which population-based family data and established risk variants exist.

Clonality of multicentric breast cancer has traditionally been difficult to assess. We aimed to assess this using analysis of TP53 status (expression and mutation status). These results were then incorporated into an analysis of prognostic factors in multicentric tumours in a 10-year follow up study. Clonal status of multicentric breast cancer foci (n = 88 foci) was determined by immunohistochemical and molecular studies of TP53 in a total of 40 patients. Prognostic factors from these patients were also compared with 80 age- and stage-matched controls with unicentric breast cancer from the Royal Marsden NHS Foundation Trust Breast Cancer Database. Our results indicate that multicentric breast cancer foci were polyclonal within an individual patient in at least 10 patients (25%) with respect to immunohistochemical staining and in four patients (10%) with respect to abnormal band shifts on single strand conformational polymorphism (SSCP) molecular analysis. No individual variable was predictive of multicentric or unicentric disease. However, there was a worse overall survival in the multicentric breast cancer patients in whom at least two cancer foci stained positively on TP53 immunohistochemistry compared with the matched control group (P = 0.04). In conclusion, these results suggest that a proportion of multicentric breast cancer foci are polyclonal with respect to TP53 status and that TP53 over-expression predicts for a poorer prognosis in multicentric breast cancer.

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens.Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk.Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 0.76 and 0.07, respectively.Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

Background: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies.Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated.Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71-1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59-1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk.Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers.Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk. Cancer Epidemiol Biomarkers Prev; 20(5); 1032-38. (C) 2011 AACR.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2.METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers.RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers. British Journal of Cancer (2011) 104, 1356-1361. doi:10.1038/bjc.2011.91 www.bjcancer.com Published online 22 March 2011 (C) 2011 Cancer Research UK

BACKGROUND: As part of the Magnetic Resonance Imaging for Breast Screening (MARIBS), Study women with a family history of breast cancer were assessed psychologically to determine the relative psychological impact and acceptability of annual screening using magnetic resonance imaging (MRI) and conventional X-ray mammography (XRM).METHODS: Women were assessed psychologically at baseline (4 weeks before MRI and XRM), immediately before, and immediately after, both MRI and XRM, and at follow-up (6 weeks after the scans).RESULTS: Overall, both procedures were found to be acceptable with high levels of satisfaction (MRI, 96.3% and XRM, 97.7%; NS) and low levels of psychological morbidity throughout, particularly at 6-week follow-up. Low levels of self-reported distress were reported for both procedures (MRI, 13.5% and XRM, 7.8%), although MRI was more distressing (P = 0.005). Similarly, higher anticipatory anxiety was reported before MRI than before XRM (P = 0.003). Relative to XRM, MRI-related distress was more likely to persist at 6 weeks after the scans in the form of intrusive MRI-related thoughts (P = 0.006) and total MRI-related distress (P = 0.014). More women stated that they intended to return for XRM (96.3%) than for MRI (88%; P < 0.0005). These effects were most marked for the first year of screening, although they were also statistically significant in subsequent years.CONCLUSION: Given the proven benefits of MRI in screening for breast cancer in this population, these data point to the urgent need to provide timely information and support to women undergoing MRI. British Journal of Cancer (2011) 104, 578-586. doi:10.1038/bjc.2011.1 www.bjcancer.com (C) 2011 Cancer Research UK

BACKGROUND: We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone.METHODS: We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N = 31 and N = 18, respectively).RESULTS: Compared with screening men based on age alone (aged 55-79: 10-year absolute risk >= 2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47-79: 10-year absolute risk >= 2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases.CONCLUSION: Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening. British Journal of Cancer (2011) 104, 1656 -1663. doi: 10.1038/bjc.2011.118 www.bjcancer.com Published online 5 April 2011 (C) 2011 Cancer Research UK

Aim: The aim of this study was to understand more fully how healthcare professionals deal with the uncertainty intrinsic in counseling and treating women from hereditary breast/ovarian cancer families who receive inconclusive BRCA1/2 genetic test results (genetic tests that do not find a mutation to account for the family history). Methods: We conducted a small, qualitative, exploratory study using open-ended semistructured interviews of 12 geneticists, genetic counselor/nurses, oncologists, gynecologists, and breast surgeons at a major UK cancer center. We asked questions about how these professionals dealt with the large amount of uncertainty raised by an inconclusive result, how they communicated the uncertainty involved, their feelings about presenting medical management options based on information fraught with uncertainty, the role of the media, differences in perspectives by specialty, and personal feelings about the uncertainty. Results: Based on themes generated by the data, we proposed the concept "ownership of uncertainty" (sole, shared, diffused, normalized, transferred) to explain how the professionals in this study dealt with this high degree of uncertainty. A shared ownership of uncertainty was the dominant model during the presentation of information given by the professionals as part of their consultation with their patients. However, the final decision for management was left primarily to the woman seeking advice, even though several of the professionals reported feeling uneasy about this. Conclusion: The concept "ownership of uncertainty" helps advance the understanding of how the healthcare professionals deal with the uncertainty intrinsic to an inconclusive BRCA1/2 genetic test result within the current social context.

Background: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent.Methods: We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci.Results: We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2.Conclusion: We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations.Impact: The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent. Cancer Epidemiol Biomarkers Prev; 20(1); 23-32. (C) 2011 AACR.

Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.

BACKGROUND: A family history of prostate cancer (PrCa) is a strong risk factor for the disease, indicating that inherited factors are important in this disease. We previously estimated that about 2% of PrCa cases diagnosed <= 55 years harbour a BRCA2 mutation and PrCa among BRCA2 carriers has been shown to be more aggressive, with poorer survival.METHODS: To further evaluate the role of BRCA2 in PrCa predisposition, we screened 1864 men with PrCa aged between 36 and 88 years. We analysed the BRCA2 gene using a novel high-throughput multiplex fluorescence heteroduplex detection system developed for the ABI3130xl genetic analyzer.RESULTS: We identified 19 protein-truncating mutations, 3 in-frame deletions and 69 missense variants of uncertain significance (UV) in our sample set. All the carriers of truncating mutations developed PrCa at <= 65 years, with a prevalence of BRCA2 mutation of 1.20% for cases in this age group.CONCLUSION: Based on the estimated frequency of BRCA2 mutations in the United Kingdom we estimate that germline mutations in the BRCA2 gene confer an similar to 8.6-fold increased risk of PrCa by age 65, corresponding to an absolute risk of similar to 15% by age 65. These results suggest that routine testing of early onset PrCa cases for germline BRCA2 mutations will further help to refine the prevalence and risk associated with BRCA2 mutations and may be useful for guiding management options. British Journal of Cancer (2011) 105, 1230-1234. doi:10.1038/bjc.2011.383 www.bjcancer.com Published online 27 September 2011 (C) 2011 Cancer Research UK

We assessed ovarian cancer screening outcomes in women with a positive family history of ovarian cancer divided into a low-, moderate- or high-risk group for development of ovarian cancer.

Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best-fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11-0.20), with a relative risk for homozygote carriers of 94 (95% CI 46-192), and a polygenic standard deviation of 2.01 (95% CI 1.72-2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non-additive effects of one or more genes.

A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio.

Genome-wide association studies have found type 2 diabetes-associated variants in the HNF1B gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only.

The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours.

Pelvic irradiation in addition to prostate irradiation may improve outcome in locally advanced prostate cancer, but is associated with dose-limiting bowel toxicity. We report the preliminary results of a dose escalation study using intensity-modulated radiotherapy.

Established prognostic factors in localized prostate cancer explain only a moderate proportion of variation in outcome. We analyzed tumor expression of apoptotic markers with respect to outcome in men with localized prostate cancer in two randomized controlled trials of radiotherapy dose escalation.

Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant and benign tissues (p<0.001). Significantly increased expression of Ki-67 occurred in prostate cancers with higher Gleason score (p<0.001). Elevated Ki-67 expression was identified in 71% of prostate cancers in BRCA1 or BRCA2 mutation carriers and in 67% of the sporadic controls (p>0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is against a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all prostate cancers occurring in the presence of BRCA germline mutations are clinically aggressive, their potentially different phenotypes consistently involve maximal rates of cell proliferation.

MSMB, a gene coding for beta-microseminoprotein, has been identified as a candidate susceptibility gene for prostate cancer (PrCa) in two genome-wide association studies (GWAS). SNP rs10993994 is 2 bp upstream of the transcription initiation site of MSMB and was identified as an associated PrCa risk variant. The MSMB protein is underexpressed in PrCa and it was previously proposed to be an independent marker for the recurrence of cancer after radical prostatectomy.

Introduction: Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.Methods: We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers.Results: SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r(2) = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P-trend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P-trend = 0.018).Conclusions: This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.

Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk.

The UK incidence of prostate cancer has been increasing in men aged < 60 years. Migrant studies and global and secular variation in incidence suggest that modifiable factors, including a high-fat diet, may contribute to prostate cancer risk. The aim of the present study was to investigate the role of dietary fat intake and its derivatives on early-onset prostate cancer risk. During 1999-2004, a population-based case-control study with 512 cases and 838 controls was conducted. Cases were diagnosed with prostate cancer when < or = 60 years. Controls were sourced from UK GP practice registers. A self-administered FFQ collected data on typical past diet. A nutritional database was used to calculate daily fat intake. A positive, statistically significant risk estimate for the highest v. lowest quintile of intake of total fat, SFA, MUFA and PUFA was observed when adjusted for confounding variables: OR 2.53 (95 % CI 1.72, 3.74), OR 2.49 (95 % CI 1.69, 3.66), OR 2.69 (95 % CI 1.82, 3.96) and OR 2.34 (95 % CI 1.59, 3.46), respectively, with all P for trend < 0.001. In conclusion, there was a positive statistically significant association between prostate cancer risk and energy-adjusted intake of total fat and fat subtypes. These results potentially identify a modifiable risk factor for early-onset prostate cancer.

BACKGROUND. Recent genome-wide association studies have shown an association of a SNP two base pairs upstream of the 5' UTR of the microseminoprotein-beta (MSMB) gene with an increased risk of developing the prostate cancer, re-igniting interest in its protein product, MSMB.METHODS. As one of the most abundant prostatic proteins, MSMB can be reliably detected in tissue and serum.RESULTS. It has been consistently shown that MSMB expression is high in normal and benign prostate tissue and lowered or lost in prostate cancer suggesting that it might be a useful tissue biomarker for prostate cancer diagnosis and its levels in serum may be useful as a marker for prognosis. Members of the cysteine-rich secretory protein family and laminin receptors have been shown to bind MSMB at the cell surface and in serum thereby regulating apoptosis. Thus, in the benign prostate, MSMB regulates cell growth, but when MSMB is lost during tumourigenesis, cells are able to grow in a more uncontrolled manner. Both full length MSMB and a short peptide comprised of amino acids 31-45 have been tested for potential therapeutic benefit in mouse models and humans.CONCLUSIONS. MSMB has potential as a biomarker of prostate cancer development, progression and recurrence and potentially as a target for therapeutic intervention. Prostate 70: 333-340, 2010. (C) 2009 Wiley-Liss, Inc.

Women from families with a high risk of breast or ovarian cancer in which genetic testing for mutations in the BRCA1/2 genes is inconclusive are a vulnerable and understudied group. Furthermore, there are no studies of the professional specialists who treat them - geneticists, genetic counsellors/nurses, oncologists, gynaecologists and breast surgeons.

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

Background: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population.Methods: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).Results: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P-trend = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P-trend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers.Conclusions: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers.Impact: The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev; 19(11); 2859-68. (C)2010 AACR.

Risk-reducing salpingo-oophorectomy (RRSO) is widely used for cancer risk reduction in BRCA1 or BRCA2 (BRCA1/2) mutation carriers. Occult ovarian/fallopian tube cancers (OOC) detected at the time of RRSO have been reported in several studies with wide variability in reported prevalence. We estimated the prevalence of OOC in a prospective cohort of 647 BRCA1/2 mutation carriers from 18 centers (PROSE consortium) who underwent RRSO between 2001 and 2008. OOC was detected in 16 of 647 women (2.5%). The mean age at RRSO was 51.7 in those with OOC versus 46.6 in those without OOC (P = 0.017). Twelve of the 16 OOCs (75%) were diagnosed in women with BRCA1 mutations. Thirty-eight percent of women with OOC had stage 1 cancer versus none of the women in the PROSE database diagnosed with ovarian cancer outside of screening. Among 385 women (60%) in whom pathology reports were available for central review, 246 (64%) RRSOs were performed at participating PROSE centers while 139 (36%) were performed at local sites. Ovarian and fallopian tube tissues removed at major genetics referral centers were significantly more likely to have been examined in toto compared to specimens obtained at non-referral centers (75% vs. 30%, P < 0.001). Our results confirm that OOC may be found at the time of RRSO in BRCA1/2 mutation carriers and suggest that OOC are of a more favorable stage than cancers found outside RRSO. An unacceptably high proportion of pathologic examinations did not adequately examine ovaries and fallopian tubes obtained at RRSO.

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).

Context Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer.Objective To estimate risk and mortality reduction stratified by mutation and prior cancer status.Design, Setting, and Participants Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009.Main Outcomes Measures Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality.Results No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, womenwho underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancerspecific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancerspecific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]).Conclusions Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. JAMA. 2010; 304(9): 967-975 www.jama.com

BACKGROUND. Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity.METHODS. We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing.RESULTS. Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM.CONCLUSIONS. Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate 70: 735-744, 2010. (C) 2010 Wiley-Liss, Inc.

Presymptomatic genetic testing in childhood for adult onset conditions is generally discouraged as it does not directly benefit the child and removes their autonomy. In certain cancer prone conditions such as Familial Adenomatous Polyposis and Von Hippel Lindau disease there are risks of disease in childhood and benefit to children not inheriting a mutation in being able to forego unpleasant screening tests. Li-Fraumeni syndrome caused by constitutional TP53 mutations there are also implications in childhood with a risk of around 20% of a childhood malignancy. However, as yet no evidence based surveillance programme has been identified. We describe our experience of childhood testing for four children in two Li-Fraumeni families caused by TP53 mutations.

There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

To review imaging features of screening-detected cancers on images from diagnostic and prior examinations to identify specific abnormalities to aid earlier detection of or facilitate differentiation of cancers in BRCA1 and BRCA2 carriers and in women with a high risk for breast cancer.

Folate-pathway gene polymorphisms have been implicated in several cancers and investigated inconclusively in relation to prostate cancer. We conducted a systematic review, which identified nine case-control studies (eight included, one excluded). We also included data from four genome-wide association studies and from a case-control study nested within the UK population-based Prostate Testing for Cancer and Treatment study. We investigated by meta-analysis the effects of eight polymorphisms: MTHFR C677T (rs1801133; 12 studies; 10,745 cases; 40,158 controls), MTHFR A1298C (rs1801131; 5 studies; 3,176 cases; 4,829 controls), MTR A2756G (rs1805087; 8 studies; 7,810 cases; 37,543 controls), MTRR A66G (rs1801394; 4 studies; 3,032 cases; 4,515 controls), MTHFD1 G1958A (rs2236225; 6 studies; 7,493 cases; 36,941 controls), SLC19A1/RFC1 G80A (rs1051266; 4 studies; 6,222 cases; 35,821 controls), SHMT1 C1420T (rs1979277; 2 studies; 2,689 cases; 4,110 controls), and FOLH1 T1561C (rs202676; 5 studies; 6,314 cases; 35,190 controls). The majority (10 of 13) of eligible studies had 100% Caucasian subjects; only one study had <90% Caucasian subjects. We found weak evidence of dominant effects of two alleles: MTR 2756A>G [random effects pooled odds ratio, 1.06 (1.00-1.12); P = 0.06 (P = 0.59 for heterogeneity across studies)] and SHMT1 1420C>T [random effects pooled odds ratio, 1.11 (1.00-1.22); P = 0.05 (P = 0.38 for heterogeneity across studies)]. We found no effect of MTHFR 677C>T or any of the other alleles in dominant, recessive or additive models, or in comparing a/a versus A/A homozygous. Neither did we find any difference in effects on advanced or localized cancers. Our meta-analysis suggests that known common folate-pathway single nucleotide polymorphisms do not have significant effects on susceptibility to prostate cancer.

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.

Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).

Mammographic breast density is one of the strongest known risk factors for breast cancer. We present a novel technique for estimating breast density based on 3D T1-weighted Magnetic Resonance Imaging (MRI) and evaluate its performance, including for breast cancer risk prediction, relative to two standard mammographic density-estimation methods.

To test the hypothesis that, in a matched series of prostatic cancers, either with or without BRCA1 or BRCA2 mutations, RAD51 protein expression is enhanced in association with BRCA mutation genotypes.

Although prostate cancer (PrCa) is one of the most common cancers in men in Western countries, little is known about the inherited factors that influence PrCa risk. On the basis of the fact that BRIP1/FANCJ interacts with BRCA1 and functions as a regulator of DNA double-strand break repair pathways, and that germline mutations within the BRIP1/FANCJ gene predispose to breast cancer, we chose this gene as a candidate for mutation screening in familial and young-onset PrCa cases. We identified a truncating mutation, R798X, in the BRIP1/FANCJ gene in 4 out of 2714 UK PrCa cases enriched for familial (2 out of 641; 0.3%) and young-onset cases (2 out of 2073; 0.1%). On screening 2045 controls from the UK population, we found one R798X sequence alteration (0.05%; odds ratio 2.4 (95% CI 0.25-23.4)). In addition, using our data from a genome-wide association study, we analysed 25 SNPs in the genomic region of the BRIP1/FANCJ gene. Two SNPs showed evidence of association with familial and young-onset PrCa (rs6504074; P(trend)=0.04 and rs8076727; P(trend)=0.01). These results suggest that truncating mutations in BRIP1/FANCJ might confer an increased risk of PrCa and common SNPs might also contribute to the alteration of risk, but larger case-control series will be required to confirm or refute this association.

To integrate the mapping of ERG alterations with the collection of expression microarray (EMA) data, as previous EMA analyses have failed to consider the genetic heterogeneity and complex patterns of ERG alteration frequently found in cancerous prostates.

Magnetic resonance imaging (MRI) is an effective method for evaluating the spine in patients with a high risk of metastatic disease. The aim of this study was to compare MRI spine with radionuclide bone scan in detecting spinal metastases for staging prostate cancer patients.

Active surveillance provides a unique opportunity to study biomarkers of prostate cancer behaviour, although only small volumes of tumor tissue are typically available. We have evaluated a technique for constructing tissue microarrays (TMAs) from needle biopsies for assessing immunohistochemical markers in localized prostate cancer managed by active surveillance. TMAs were constructed from diagnostic prostate biopsies for 60 patients with localized prostatic adenocarcinoma in a prospective cohort study of active surveillance. Radical treatment was recommended for a prostate-specific antigen (PSA) velocity greater than 1 ng ml(-1) per year or adverse histology in repeat biopsies, defined as Gleason score > or =4+3 or >50% of cores involved. Sections from the TMAs were stained with H&E, P63/AMACR and Ki-67. Time to radical treatment was analysed with respect to clinical characteristics and Ki-67 LI. At a median follow up of 36 months, 25/60 (42%) patients had received radical treatment. On univariate analysis, PSA density (P=0.001), Gleason score (P=0.001), clinical T stage (P=0.01), Ki-67 LI (P=0.02) and initial PSA (P=0.04) were associated with time to radical treatment. On multivariate analysis, PSA density (P=0.01), Ki-67 LI (P=0.03) and Gleason score (P=0.04) were independent determinants of progression to radical treatment. TMAs constructed from prostate needle biopsies can be used to assess immunohistochemical markers in localized prostate cancer managed by active surveillance. Ki-67 LI merits further study as a possible biomarker of early prostate cancer behaviour.

Introduction Interest in searching for mutations in BRCA1 and BRCA2 is high. Knowledge regarding these genes and the advantages and limitations of genetic testing is limited. It is unknown whether increasing knowledge about breast cancer genetic testing alters interest in testing. Methods Three hundred and seventy nine women (260 with a family history of breast cancer; 119 with breast cancer) from The Royal Marsden NHS Foundation Trust were randomised to receive or not receive written educational information on cancer genetics. A questionnaire was completed assessing interest in BRCA1 testing and knowledge on breast cancer genetics and screening. Actual uptake of BRCA1 testing is reported with a six year follow-up. Results Eighty nine percent of women at risk of breast cancer and 76% of women with breast cancer were interested in BRCA1 testing (P < 0.0001). Provision of educational information did not affect level of interest. Knowledge about breast cancer susceptibility genes was poor. According to the NICE guidelines regarding eligibility for BRCA1 and BRCA2 testing, the families of 66% of the at risk group and 13% of the women with breast cancer would be eligible for testing (probability of BRCA1 mutation a parts per thousand yen20%). Within six years of randomisation, genetic testing was actually undertaken on 12 women, only 10 of whom would now be eligible, on the NICE guidelines. Conclusions There is strong interest in BRCA1 testing. Despite considerable ignorance of factors affecting the inheritance of breast cancer, education neither reduced nor increased interest to undergo testing. The NICE guidelines successfully triage those with a high breast cancer risk to be managed in cancer genetics clinics.

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

BACKGROUND: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T > G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.METHODS: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T > G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.RESULTS: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR) = 1.01, 95% confidence interval (CI): 0.93-1.10, P-trend = 0.77; MDM2: HR = 0.96, 95% CI: 0.84-1.09, P-trend = 0.54) or for BRCA2 mutation carriers (TP53: HR = 0.99, 95% CI: 0.87-1.12, P-trend = 0.83; MDM2: HR = 0.98, 95% CI: 0.80-1.21, P-trend = 0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.CONCLUSION: There was no evidence that TP53 Arg72Pro or MDM2 309T > G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers. British Journal of Cancer (2009) 101, 1456-1460. doi: 10.1038/sj.bjc.6605279 www.bjcancer.com Published online 25 August 2009 (C) 2009 Cancer Research UK

GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (P (trend) = 0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [Garcia-Closas M et al. (2007) Cancer Epidemiol Biomarkers Prev 16:2269-2275]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (ORper-allele = 1.00, 95% CI 0.94-1.05), in ER negative BCAC cases (ORper-allele = 1.02, 95% CI 0.91-1.13), in BRCA1 mutation carriers RRper-allele = 0.99, 95% CI 0.90-1.09) or BRCA2 mutation carriers (RRper-allele = 0.93, 95% CI 0.80-1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women.

Whole-body MRI is an effective method for evaluating the entire skeletal system in patients with metastatic disease. This study aimed to compare whole-body MRI and radionuclide bone scintigraph in the detection of skeletal metastases in patients with prostate cancer. Patients with prostate cancer at high risk of skeletal metastasis with (i) prostate-specific antigen of >= 50 ng/mL; (ii) composite Gleason score of >= 8 with prostate-specific antigen of >20 ng/mL; or (iii) node-positive disease were enrolled in this prospective study before systemic treatment was initiated. Whole-body MR images and bone scans of 39 patients were analysed. Seven patients had bone metastases on bone scans, while seven patients had skeletal metastases by whole-body MRI, with concordant findings only in four patients. Compared with the 'gold standard', derived from clinical and radiological follow-up, the sensitivity for both bone scans and MRI was 70%, and the specificity for both was 100%. Magnetic resonance imaging detected 26 individual lesions compared with 18 lesions on bone scans. Only eight lesions were positive on both. Bone scans detected more rib metastases, while MRI identified more metastatic lesions in the spine. Whole-body MRI and radionuclide bone scintigraphy have similar specificity and sensitivity and may be used as complementary investigations to detect skeletal metastases from prostate cancer.

Introduction: A UK multicenter study compared the performance of contrast enhanced-magnetic resonance imaging with X-Ray Mammography in women at high-risk of breast cancer commencing in 1997. Selection criteria were used to identify women with at least 0.9% annual risk of breast cancer.Methods: Women at high breast cancer risk, with a strong family history and/or high probability of a BRCA1/BRCA2/TP53 mutation, were recruited from 22 centers. Those not known as gene carriers were asked to give a blood sample, which was tested anonymously for mutations. Women ages 35 to 49 years were offered annual screening for 2 to 7 years. Study eligibility at entry was assessed retrospectively by detailed examination of pedigrees and overall eligibility accounting for computer risk assessment and mutation results.Results: Seventy-eight of 837 (9%) women entered for screening were ineligible using the strict entry criteria. Thirty-nine cancers were detected in 1,869 women-years in study (incidence 21 per 1,000). Including 3,561 further years follow-up, 28 more breast cancers were identified (12 of 1,000). Incidence rates for 759 eligible women were 22 of 1,000 in study and 13 of 1,000 in total follow-up, compared with 9 of 1,000 and 4 of 1,000, respectively, in 78 ineligible women. Breast cancer rates were higher for BRCA2 than BRCA1 after testing anonymized samples in this selected population at 65 of 1,000 in study and 36 of 1,000 in total follow-up for BRCA2 compared with 44 of 1,000 and 27 of 1,000 for BRCA1.Conclusions: Strict enforcement of study criteria would have minimally improved the power of the study, whereas testing for BRCA1/2 in advance would have substantially increased the detection rates. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2123-31)

To examine, in a case-control study, the association between the frequency of sexual activity (intercourse, masturbation, overall) and prostate cancer risk in younger men diagnosed at < or = 60 years old.

Lynch Syndrome/HNPCC is a syndrome of cancer predisposition linked to inherited mutations of genes participating in post-replicative DNA mismatch repair (MMR). The spectrum of cancer associated with Lynch Syndrome includes tumours of the colorectum, endometrium, ovary, upper gastrointestinal tract and the urothelium although other cancers are rarely described. We describe a family of Lynch Syndrome with an hMLH1 mutation, that harbours an unusual tumour spectrum and its diagnostic and management challenges.

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron I of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers.CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. British Journal of Cancer (2009) 101, 2048-2054. doi: 10.1038/sj.bjc.6605416 www.bjcancer.com Published online 17 November 2009 (C) 2009 Cancer Research UK

Genetic predisposition to prostate cancer includes multiple common variants with a low penetrance (single nucleotide polymorphisms) and rare variants with higher penetrance. The mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 are associated with Lynch syndrome where colon and endometrial cancers are the predominant phenotypes. The purpose of our study was to investigate whether germ-line mutations in these genes may be associated with prostate cancer. One hundred and six male carriers or obligate carriers of MMR mutations were identified. Nine had contracted prostate cancer. Immunohistochemical analysis was done on tumor tissue from eight of the nine tumors. Observed incidence, cumulative risk at 60 and 70 years of age, age of onset, and Gleason score were compared with expected as assessed from population-based series. Absence of gene product from the mutated MMR gene was found in seven of eight tumors. Expected number of prostate cancers was 1.52 compared with 9 observed (P < 0.01). Mean age of onset of prostate cancer was 60.4 years compared with 66.6 expected (P = 0.006); the number of men with a Gleason score between 8 and 10 was significantly higher than expected (P < 0.00001). Kaplan-Meier analysis suggested that cumulative risk by 70 years in MMR mutation carriers may be 30% (SE, 0.088) compared with 8.0% in the general population. This is similar to the high risk associated with BRCA2 mutations. To our knowledge, this study is the first to indicate that the MMR genes may be among the rare genetic variants that confer a high risk of prostate cancer when mutated. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2460-7)

We present a case of dramatic response of poor prognosis cancer in a lady with a germline mutation in the BRCA2 gene who was exposed to platinum containing chemotherapy. She is cancer-free 10 years' later. Such cases provide clinical scenarios for the basis of trials of platinum-like agents in individuals with BRCA mutations who develop cancer. Moule, R. et al. (2009). Clinical Oncology 21, 444-447 (C) 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Background: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (00 use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated in a small number of studies. Methods: We used data on 2,281. BRCA1. carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox proportional hazards framework. Results: There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had ever used OC were at a significantly reduced risk of developing ovarian cancer (hazard ratio, 0.52; 95% confidence intervals, 0.37-0.73; P = 0.0002) and increasing duration of OC use was associated with a reduced ovarian cancer risk (P trend = 0.0004). The protective effect of OC use for BRCA1 mutation carriers seemed to be greater among more recent users. Tubal ligation was associated with a reduced risk of ovarian cancer for BRCA1 carriers (hazard ratio, 0.42; 95% confidence intervals, 0.22-0.80; P = 0.008). The number of ovarian cancer cases in BRCA2 mutation carriers was too small to draw definitive conclusions. Conclusions: The results provide further confirmation that OC use, number of full-term pregnancies, and tubal ligation are associated with ovarian cancer risk in BRCA1 carriers to a similar relative extent as in the general population. (Cancer Epidemiol Biomarkers Prev 2009;18(2):601-10)

Germline mutations in the mismatch repair (MMR) genes are associated with Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Here, we characterise a variant of hMLH1 that confers a loss-of-function MMR phenotype. The mutation changes the highly conserved Gly67 residue to a glutamate (G67E) and is reminiscent of the hMLH1-p. Gly67Arg mutation, which is present in several Lynch syndrome cohorts. hMLH1-Gly67Arg has previously been shown to confer loss-of-function (Shimodaira et al, 1998), and two functional assays suggest that the hMLH1-Gly67Glu protein fails to sustain normal MMR functions. In the first assay, hMLH1-Gly67Glu abolishes the protein's ability to interfere with MMR in yeast. In the second assay, mutation of the analogous residue in yMLH1 (yMLH1-Gly64Glu) causes a loss-of-function mutator phenotype similar to yMLH1-Gly64Arg. Despite these molecular similarities, an unusual spectrum of tumours is associated with hMLH1-Gly67Glu, which is not typical of those associated with Lynch syndrome and differs from those found in families carrying the hMLH1-Gly67Arg allele. This suggests that hMLH1 may have different functions in certain tissues and/or that additional factors may modify the influence of hMLH1 mutations in causing Lynch syndrome.

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at </=60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 x 10(-8) to P = 8.7 x 10(-29)). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.

Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers.

Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR of 0.89 (95% CI 0.65-1.12, P=0.25) and 1.11 (95% CI 0.81-1.52, P=0.53) for the null alleles of GSTM1 and GSTT1, respectively. For GSTP1, HR for BC was 1.36 (95% CI 1.02-1.81, P=0.04) for individuals with Ile/Val, and 2.00 (95% CI 1.18-3.38) for carriers of the Val/Val genotype (P=0.01). An HR of 3.20 (95% CI 1.26-8.09, P=0.01), and younger age at BC onset (P=0.2), were found among Val/Val, BRCA2 carriers, but not among BRCA1 carriers. In conclusion, our results indicate significantly elevated risk for BC in carriers of BRCA2 mutations with GSTP1-Val allele with dosage effect, as implicated by higher risk in homozygous Val carriers. The GSTM1- and GSTT1-null allele did not seem to have a major effect.

Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.

Genome-wide association studies (GWAS) provide a powerful approach to identify common, low-penetrance disease loci without prior knowledge of location or function. GWAS have been conducted in five of the commonest cancer types: breast, prostate, colorectal and lung, and melanoma, and have identified more than 20 novel disease loci, confirming that susceptibility to these diseases is polygenic. Many of these loci were detected at low power, indicating that many further loci will probably be detected with larger studies. For the most part, the loci were not previously suspected to be related to carcinogenesis, and point to new disease mechanisms. The risks conferred by the susceptibility alleles are low, generally 1.3-fold or less. The combined effects may, however, be sufficiently large to be useful for risk prediction, and targeted screening and prevention, particularly as more loci are identified.

Several prostate cancer susceptibility loci have recently been identified by genome-wide association studies. These loci are candidates for susceptibility to other epithelial cancers. The aim of this study was to test these tag single nucleotide polymorphisms (SNP) for association with invasive ovarian, colorectal, and breast cancer. Twelve prostate cancer-associated tag SNPs were genotyped in ovarian (2,087 cases/3,491 controls), colorectal (2,148 cases/2,265 controls) and breast (first set, 4,339 cases/4,552 controls; second set, 3,800 cases/3,995 controls) case-control studies. The primary test of association was a comparison of genotype frequencies between cases and controls, and a test for trend stratified by study where appropriate. Genotype-specific odds ratios (OR) were estimated by logistic regression. SNP rs2660753 (chromosome 3p12) showed evidence of association with ovarian cancer [per minor allele OR, 1.19; 95% confidence interval (95% CI), 1.04-1.37; P(trend) = 0.012]. This association was stronger for the serous histologic subtype (OR, 1.29; 95% CI, 1.09-1.53; P = 0.003). SNP rs7931342 (chromosome 11q13) showed some evidence of association with breast cancer (per minor allele OR, 0.95; 95% CI, 0.91-0.99; P(trend) = 0.028). This association was somewhat stronger for estrogen receptor-positive tumors (OR, 0.92; 95% CI, 0.87-0.98; P = 0.011). None of these tag SNPs were associated with risk of colorectal cancer. In conclusion, loci associated with risk of prostate cancer may also be associated with ovarian and breast cancer susceptibility. However, the effects are modest and warrant replication in larger studies.

PurposeWe evaluated the clinical impact of germ-line BRCA1/2 mutations in patients with epithelial ovarian cancer (EOC) on responses to first and subsequent lines of chemotherapy, treatment-free interval (TFI) between each line of therapy, and overall survival (OS).Patients and MethodsTwenty-two EOC patients with germ-line BRCA1 or BRCA2 mutations (BRCA-positive) were selected from our database and matched (1: 2) with 44 nonhereditary EOC controls (defined by no associated personal history of breast cancer and no family history of breast and ovarian cancer or an uninformative BRCA mutation test) for stage, histologic subtype, age, and year of diagnosis. All patients received primary platinum-based chemotherapy. Statistical comparisons included responses after first-, second-, and third-line treatment (chi(2)/Fisher's exact test) and median OS (Kaplan-Meier method/log-rank test).ResultsCompared with controls, BRCA-positive patients had higher overall (95.5% v 59.1%; P = .002) and complete response rates (81.8% v 43.2%; P = .004) to first line treatment, higher responses to second and third line platinum-based chemotherapy (second line, 91.7% v 40.9% [P = .004]; third line, 100% v 14.3% [P = .005]) and longer TFIs. A significant improvement in median OS in BRCA-positive patients compared with controls was observed from both time of diagnosis (8.4 v 2.9 years; P < .002) and time of first relapse (5 v 1.6 years; P < .001). BRCA status, stage, and length of first response were independent prognostic factors from time of first relapse.ConclusionBRCA-positive EOC patients have better outcomes than nonhereditary EOC patients. There exists a clinical syndrome of BRCAness that includes serous histology, high response rates to first and subsequent lines of platinum-based treatment, longer TFIs between relapses, and improved OS.

Prostate cancer is the most frequently diagnosed male cancer, and its clinical outcome is difficult to predict. The disease may involve the inappropriate expression of genes that normally control the proliferation of epithelial cells in the basal layer and their differentiation into luminal cells. Our aim was to identify novel basal cell markers and assess their prognostic and functional significance in prostate cancer. RNA from basal and luminal cells isolated from benign tissue by immunoguided laser-capture microdissection was subjected to expression profiling. We identified 112 and 267 genes defining basal and luminal populations, respectively. The transcription factor TEAD1 and the ubiquitin ligase c-Cbl were identified as novel basal cell markers. Knockdown of either marker using siRNA in prostate cell lines led to decreased cell growth in PC3 and disrupted acinar formation in a 3D culture system of RWPE1. Analyses of prostate cancer tissue microarray staining established that increased protein levels of either marker were associated with decreased patient survival independent of other clinicopathological metrics. These data are consistent with basal features impacting on the development and clinical course of prostate cancers.

There is a high and rising prevalence of prostate cancer (PRCA) within the male population of the United Kingdom. Although the relative risk of PRCA is higher in male BRCA2 and BRCA1 mutation carriers, the histological characteristics of this malignancy in these groups have not been clearly defined. We present the histopathological findings in the first UK series of BRCA1 and BRCA2 mutation carriers with PRCA. The archived histopathological tissue sections of 20 BRCA1/2 mutation carriers with PRCA were collected from histopathology laboratories in England, Ireland and Scotland. The cases were matched to a control group by age, stage and serum PSA level of PRCA cases diagnosed in the general population. Following histopathological evaluation and re-grading according to current conventional criteria, Gleason scores of PRCA developed by BRCA1/2 mutation carriers were identified to be significantly higher (Gleason scores 8, 9 or 10, P=0.012) than those in the control group. Since BRCA1/2 mutation carrier status is associated with more aggressive disease, it is a prognostic factor for PRCA outcome. Targeting screening to this population may detect disease at an earlier clinical stage which may therefore be beneficial.

Translocation of TMPRSS2 to the ERG gene, found in a high proportion of human prostate cancer, results in overexpression of the 3'-ERG sequences joined to the 5'-TMPRSS2 promoter. The studies presented here were designed to test the ability of expression analysis on GeneChip Human Exon 1.0 ST arrays to detect 5'-TMPRSS2-ERG-3' hybrid transcripts encoded by this translocation. Monitoring the relative expression of each ERG exon revealed altered transcription of the ERG gene in 15 of a series of 27 prostate cancer samples. In all cases, exons 4 to 11 exhibited enhanced expression compared with exons 2 and 3. This pattern of expression indicated that the most abundant hybrid transcripts involve fusions to ERG exon 4, and RT-PCR analyses confirmed the joining of TMPRSS2 exon 1 to ERG exon 4 in all 15 cases. The exon expression patterns also indicated that TMPRSS2-ERG fusion transcripts commonly contain deletion of ERG exon 8. Analysis of gene-level data from the arrays allowed the identification of genes whose expression levels significantly correlated with the presence of the translocation. These studies demonstrate that expression analyses using exon arrays represent a valuable approach for detecting ETS gene translocation in prostate cancer, in parallel with analyses of gene expression profiles.

An ERG gene 'break-apart' fluorescence in situ hybridization (FISH) assay has been used to screen whole-mount prostatectomy specimens for rearrangements at the ERG locus. In cancers containing ERG alterations the observed pattern of changes was often complex. Different categories of ERG gene alteration were found either together in a single cancerous region or within separate foci of cancer in the same prostate slice. In some cases the juxtaposition of particular patterns of ERG alterations suggested possible mechanisms of tumour progression. Prostates harbouring ERG alterations commonly also contained cancer that lacked rearrangements of the ERG gene. A single trans-urethral resection of the prostate specimen examined harboured both ERG and ETV1 gene rearrangements demonstrating that the observed complexity may, at least in part, be explained by multiple ETS gene alterations arising independently in a single prostate. In a search for possible precursor lesions clonal ERG rearrangements were found both in high grade prostatic intraepithelial neoplasia (PIN) and in atypical in situ epithelial lesions consistent with the diagnosis of low grade PIN. Our observations support the view that ERG gene alterations represent an initiating event that promotes clonal expansion initially to form regions of epithelial atypia. The complex patterns of ERG alteration found in prostatectomy specimens have important implications for the design of experiments investigating the clinical significance and mechanism of development of individual prostate cancers.

Purpose: A method and computer tool to estimate percentage magnetic resonance (MR) imaging (MRI) breast density using three-dimensional T-1-weighted MRI is introduced, and compared with mammographic percentage density [X-ray mammography (XRM)].Materials and Methods: Ethical approval and informed consent were obtained. A method to assess MRI breast density as percentage volume occupied by water-containing tissue on three-dimensional T-1-weighted MR images is described and applied in a pilot study to 138 subjects who were imaged by both MRI and XRM during the Magnetic Resonance Imaging in Breast Screening study. For comparison, percentage mammographic density was measured from matching XRMs as a ratio of dense to total projection areas scored visually using a 21-point score and measured by applying a two-dimensional interactive program (CUMULUS). The MRI and XRM percent methods were compared, including assessment of left-right and interreader consistency.Results: Percent MRI density correlated strongly (r = 0.78; P < 0.0001) with percent mammographic density estimated using Cumulus. Comparison with visual assessment also showed a strong correlation. The mammographic methods overestimate density compared with MRI volumetric assessment by a factor approaching 2.Discussion: MRI provides direct three-dimensional measurement of the proportion of water-based tissue in the breast. It correlates well with visual and computerized percent mammographic density measurements. This method may have direct application in women having breast cancer screening by breast MRI and may aid in determination of risk.

Exposure to ionising radiation is an established risk factor for many cancers. We conducted a case-control study to investigate whether exposure to low dose ionisation radiation from diagnostic x-ray procedures could be established as a risk factor for prostate cancer. In all 431 young-onset prostate cancer cases and 409 controls frequency matched by age were included. Exposures to barium meal, barium enema, hip x-rays, leg x-rays and intravenous pyelogram (IVP) were considered. Exposures to barium enema (adjusted odds ratio (OR) 2.06, 95% confidence interval (CI) 1.01-4.20) and hip x-rays (adjusted OR 2.23, 95% CI 1.42-3.49) at least 5 years before diagnosis were significantly associated with increased prostate cancer. For those with a family history of cancer, exposures to hip x-rays dating 10 or 20 years before diagnosis were associated with a significantly increased risk of prostate cancer: adjusted OR 5.01, 95% CI 1.64-15.31 and adjusted OR 14.23, 95% CI 1.83-110.74, respectively. Our findings show that exposure of the prostate gland to diagnostic radiological procedures may be associated with increased cancer risk. This effect seems to be modified by a positive family history of cancer suggesting that genetic factors may play a role in this risk association.

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, P-trend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, P-trend = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Expression of intrinsic markers of tumour hypoxia and angiogenesis are important predictors of radiotherapeutic, and possibly surgical, outcome in several cancers. Extent of tumour hypoxia in localised prostate cancer is comparable to that in other cancers, but few data exist on the association of extent of tumour hypoxia with treatment outcome. We aimed to study the predictive value of intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer, both in patients treated with radiotherapy and in those treated surgically.

Objectives: This study explores communication within families of clinically significant genetics research results, after the death of the patient participant. BRCA2 mutations were found in several men after their death from prostate cancer. Spouses were given the results in a genetic counselling, session and asked to inform relatives.Methods: Cross-sectional, qualitative exploratory study. Interviews with 13 relatives, including informers and recipients of the information, were analysed using interpretative phenomenological analysis.Results: Dissemination was hampered when communication channels between relatives were limited, because of family rifts or socially distant or problematic relationships. When informing other branches of the family, relatives approached individuals in the generation of the deceased man, regardless of their risk status, who were then responsible for informing younger relatives. Most people informed by a relative did not seek genetic counselling. The informing relative may not have sufficient authority for the information either to be taken seriously or to challenge individual constructions about the aetiology of cancer. This impeded information transmission to further at-risk relatives. Most participants knew of relatives who bad not been told about their cancer risk.Conclusions: The implications of this limited efficiency of information transfer among relatives are discussed in the context of a potential role for genetics services in contacting at-risk relatives directly. Copyright (C) 2008 John Wiley & Sons, I.td.

The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at diagnosis of first CRC in MSH6 mutation families was 59 years compared to 45 years in both MLH1 and MSH2 mutation families. The relative risk (RR) of endometrial cancer was 55 in MSH2 mutation families, compared with 27 in MLH1 mutation families, and 37 in MSH6 mutation families; median age at diagnosis 49 years. Even within MSH2 families, endometrial cancer tended to cluster, with 28 of the 58 cases coming from families with three or more cases (P < 0.001). Absolute risk of endometrial cancer in MLH1 families was still greater than any other cancer (other than CRC). 5% of cancers in both MLH1 and MSH2 mutation families were gastric (RR = 12); 53% of these were diagnosed before 50 years. Seven cases of small intestinal cancer occurred in MSH2 and MLH1 mutation families (RR = 26). There were 13 cases of cancer of the ureter; all were in MSH2 families. These cancers tended to cluster within families (P < 0.001); three of seven families with urothelial cancer had such cases in two or more individuals; two others had kidney cancer. Nineteen of 27 ovarian cancers (70%) were in MSH2 mutation families and 70% of these were diagnosed before age 50 years. There were 9 cases of sebaceous skin cancer, 3 in two MLH1 and 6 in four MSH2 mutation families. Of 22 pancreatic cancers, 14 were known to be diagnosed before 60 years. Breast cancer RR was 1.7 overall. The type of mutation (truncating or other type, and site of mutation) showed no obvious correlation with the presence or absence of extra-colonic cancers in families.

We report a patient with Bloom syndrome, a rare autosomal recessive condition characterised by chromosomal instability leading to a high risk of cancer at an early age. The diagnosis should be considered in patients with any cancer of significantly early onset, short stature and a photosensitive lupus-like rash on the face. Diagnostic confirmation is obtained from chromosome studies that show significantly increased numbers of sister chromatid exchanges. There are important management implications, including minimising the use of ionising radiation in surveillance and treatment.

Aims: The assessment of the risk of developing cancer is largely based on family history. This study aimed to confirm as many cancer diagnoses as possible in families of patients with second primary tumours after index squamous cell carcinoma of the head, single squamous cell carcinoma and spouse controls.Materials and methods: Eighty patients with second primary tumours, 67 with single squamous cell carcinoma and 47 spouse controls were recruited into the study. A detailed interview was undertaken on ail study participants, including information on all first-degree relatives for causes of death and possible diagnoses of cancer.Results: Details were available from 1340 first-degree relatives: second primary tumour group 570 relatives, single squamous cell carcinoma 429 relatives and the spouse controls 341 relatives. There were 174 cases of cancer (76, 56 and 42, respectively). For those relatives that had died, submissions were made to the Office of National Statistics to confirm the cause and date of death. One hundred and thirty-three cases were submitted for Office of National Statistics flagging (58, 42 and 33, respectively). Seventy-four of the first-degree relatives with cancer were successfully traced. Tracing confirmed a cancer diagnosis but no further details of the primary site in 31 of the relatives. Thirty-eight of the first-degree relatives were confirmed to have the cancer site of diagnosis reported by the study participants. Thirteen of the reported diagnoses in the first-degree relatives were inaccurate with regard to the cancer site of origin. Five of the first-degree relatives did not have a cancer diagnosis confirmed on the death certificate.Conclusions: This study highlights the difficulties encountered in confirming cancer diagnoses among first-degree relatives within this cancer site. To improve such studies and our routine collection of data within the clinic setting, more robust systems are needed to interlink cancer registries, population data and hospital records.

Female germline BRCA gene mutation carriers are at increased risk for developing breast cancer. The purpose of our study was to establish whether healthy BRCA mutation carriers demonstrate an increased frequency of aberrant gene promoter hypermethylation in ductal lavage (DL) fluid, compared with predictive genetic test negative controls, that might serve as a surrogate marker of BRCA1/2 mutation status and/or breast cancer risk.

Germline mutations in the TP53 tumour suppressor gene are associated with Li-Fraumeni syndrome, which is characterised by a spectrum of neoplasms occurring in children and young adults that predominantly include early-onset breast cancer, a variety of sarcomas, brain tumours and adrenocortical tumours. The identification of patients carrying TP53 mutations is primarily based on a positive family history of these early-onset characteristic cancer types. The aim of this study is to emphasize the importance of TP53 molecular testing in patients with very early onset breast cancer and no family history of cancer.

PURPOSE Earlier studies have shown that endogenous gonadal hormones play an important role in the etiology of breast cancer among BRCA1/2 mutation carriers. So far, little is known about the safety of exogenous hormonal use in mutation carriers. In this study, we examined the association between oral contraceptive use and risk of breast cancer among BRCA1/2 carriers. PATIENTS AND METHODS In the International BRCA1/2 Carrier Cohort study (IBCCS), a retrospective cohort of 1,593 BRCA1/2 mutation carriers was analyzed with a weighted Cox regression analysis. Results We found an increased risk of breast cancer for BRCA1/2 mutation carriers who ever used oral contraceptives (adjusted hazard ratio [HR] = 1.47; 95% CI, 1.16 to 1.87). HRs did not vary according to time since stopping use, age at start, or calendar year at start. However, a longer duration of use, especially before first full-term pregnancy, was associated with an increased risk of breast cancer for both BRCA1 and BRCA2 mutation carriers (4 or more years of use before first full-term pregnancy: HR = 1.49 [95% CI, 1.05 to 2.11] for BRCA1 carriers and HR = 2.58 [95% CI, 1.21 to 5.49] for BRCA2 carriers). CONCLUSION No evidence was found among BRCA1/2 mutation carriers that current use of oral contraceptives is associated with risk of breast cancer more strongly than is past use, as is found in the general population. However, duration of use, especially before first full-term pregnancy, may be associated with an increasing risk of breast cancer among both BRCA1 and BRCA2 mutation carriers.

To conduct a pilot population-based study within a general practice catchment area to determine whether the incidence of breast cancer was increased in the Ashkenazi population.

Retrospective analysis in 150 patients with metastatic prostate cancer was conducted to determine whether early detection with MRI spine and treatment of clinically occult spinal cord compromise (SCC) facilitate preservation of neurologic function. Our results suggest that prophylactic radiotherapy for patients with back pain or radiological SCC without neurologic deficit may facilitate preservation of neurologic function. Thus MRI surveillance for SCC may be important for prostate cancer patients with bone metastases.

A proteomic approach to nipple aspiration fluid (NAF) has been used in a number of studies comparing women with breast cancer and healthy women. However, to make useful comparisons between women with breast cancer and healthy women it is necessary to establish whether there is physiological variation in the proteomic profiles of NAF. The purpose of this study was, for the first time, to examine how the proteomic profile of NAF using surface-enhanced laser desorption ionisation time-of-flight mass spectrometry varies across the menstrual cycle in healthy pre-menopausal women. Twelve women were recruited and nipple aspiration was carried out weekly from both breasts of each subject for two menstrual cycles. Matching serum samples for luteinising hormone, follicle stimulating hormone and oestradiol were obtained at each aspiration attempt. Statistically significant peaks were found for three healthy volunteers (p < 0.05). However, the peaks that varied across the menstrual cycle were different from one healthy volunteer to another and the differences were small compared with the large variation in proteomic profiles between healthy volunteers. This study provides proof of concept that the NAF proteomic profile does not vary substantially during the menstrual cycle and that therefore it is valid to compare NAF profiles from pre-menopausal women that have been taken at different stages in the menstrual cycle.

TMPRSS2-ERG gene fusions have recently been reported to be present in a high proportion of human prostate cancers. In the current study, we show that great diversity exists in the precise structure of TMPRSS2-ERG hybrid transcripts found in human prostates. Fourteen distinct hybrid transcripts are characterized, each containing different combinations of sequences from the TMPRSS2 and ERG genes. The transcripts include two that are predicted to encode a normal full-length ERG protein, six that encode N-terminal truncated ERG proteins and one that encodes a TMPRSS2-ERG fusion protein. Interestingly, distinct patterns of hybrid transcripts were found in samples taken from separate regions of individual cancer-containing prostates, suggesting that TMPRSS2-ERG gene fusions may be arising independently in different regions of a single prostate.

We have analysed the pedigrees of all 70 women who developed cancer in the Royal Marsden Hospital (RMH) tamoxifen chemoprevention trial, using the Claus model, to assess breast cancer susceptibility heterozygote risk (HR) and screened the entire coding regions of BRCA1 and 2 genes in 62 of these cases. We found a reduced incidence of breast cancers developing on tamoxifen in women who have a lower HR, but not in women with higher HR. There were too few BRCA1/2 mutations (4 cases) to be able to determine the efficacy of tamoxifen by BRCA status. Immunohistochemical analysis showed a significantly lower frequency of median ER (p=0.03) in the cancers developing in tamoxifen-treated patients. These results suggest that tamoxifen is less likely to be effective at reducing breast cancers which are ER negative and also in some individuals at higher HR.

There is conflicting evidence as to whether individuals who are heterozygous for germ-line BRCA1 or BRCA2 mutations have an altered phenotypic cellular response to irradiation. To investigate this, chromosome breakage and apoptotic response were measured after irradiation in peripheral blood lymphocytes from 26 BRCA1 and 18 BRCA2 mutation carriers without diagnosed breast cancer, and 38 unaffected age, ethnically and sex-matched controls. To assess the role of BRCA1 and BRCA2 in homologous recombination, an S phase enrichment chromosome breakage assay was used. BrdUrd incorporation studies allowed verification of the correct experimental settings. We found that BRCA1 mutation carriers without cancer had increased chromosome breaks as well as breaks and gaps per cell post irradiation using the classical G2 assay (p = 0.01 and 0.004, respectively) and the S phase enrichment assay (p = 0.01 and 0.01, respectively) compared to age-matched unaffected controls. BRCA.2 mutation carriers without cancer bad increased breaks as well as breaks and gaps per cell post irradiation using the S phase enrichment assay (p = 0.045 and 0.012, respectively). No difference was detected using the G2 assay (p = 0.88 and 0.40 respectively). BRCA1 and BRCA2 mutation carriers had normal cell cycle kinetics and apoptotic response to irradiation compared to age-matched controls. Our results show a demonstrable impairment in irradiation induced DNA repair in women with heterozygous germline BRCA1 and BRCA2 mutations prior to being diagnosed with breast cancer.

This prospective multicentre study assesses long-term impact of genetic testing for breast/ovarian cancer predisposition in a clinical cohort. Areas evaluated include risk management, distress and insurance problems 3 years post-testing. Participants are adults unaffected with cancer from families with a known BRCA1/2 mutation. One hundred and ninety-three out of 285 (70% response) participants at nine UK clinical genetics centres completed assessments at 3 years: 80% female; 37% carriers of a BRCA1/2 mutation. In the 3 years, post-genetic testing carriers reported more risk management activities than non-carriers. Fifty-five per cent of female carriers opted for risk reducing surgery; 43% oophorectomy; and 34% mastectomy. Eighty-nine per cent had mammograms compared with 47% non-carriers. Thirty-six per cent non-carriers >= 50 years did not have a mammogram post-test. Twenty-two per cent male carriers had colorectal and 44% prostate screening compared with 5 and 19% non-carriers respectively. Seven per cent carriers and 1% non-carriers developed cancer. Distress levels did not differ in carriers and non- carriers at 3-year follow-up. Forty per cent of female carriers reported difficulties with life and/or health insurance. Given the return to pre-test levels of concern among female non- carriers at 3 years and a substantial minority not engaging in recommended screening, there appears to be a need to help some women understand the meaning of their genetic status.

We have conducted a telelink telephone-led cancer genetic counselling model at The Royal Marsden NHS Foundation Trust. The study commenced in March 2004 and evaluation of the clinic was conducted over 17 months from March 2005 to the end of July 2006. A total of 612 patients had telephone consultations during this time, 228 of whom were referred from primary care with a median of 30 patients counselled per month (range of 19-63, depending on staff availability with average of two staff per clinic). Waiting times were measured for General Practitioner referrals and all 228 were counselled within the national target-stipulated 13 weeks (median 6 weeks, range 1-12). An additional 132 patients who were sent appointment letters after receipt of their family history questionnaires did not attend their appointments (18% of all potential referrals) and required recontacting by letter. After telephone counselling, 42% of patients were able to be discharged from the telephone clinic without a subsequent face-to-face appointment, thereby saving resources. The telephone clinic also had a short set-up time with flexibility on timing and day of administration, which would be an advantage in centres where outreach clinic facilities are scarce. The telelink telephone counselling model is highly efficient in triaging high risk individuals for face-to-face counselling as per the Kenilworth model, in effecting concentration of resources and in providing a flexible individual-centred approach to cancer genetic counselling delivery.

Background: Women with BRCA1 or BRCA2 (BRCA1/2) mutations can reduce cancer incidence and mortality by using bilateral prophylactic oophorectomy (BPO) or bilateral prophylactic mastectomy (BPM). The availability of these risk-reduction strategies is an important consideration in the decision to undergo genetic testing. Patients and Methods: We evaluated the use of BPO and BPM in a prospective sample of 537 female BRCA1/2 mutation carriers from 17 centers in North America and Europe. These women were aged > 30 years, had no BPM, BPO, breast cancer, or ovarian cancer before the disclosure of their genetic test results and were followed for > 6 months. Results: Bilateral prophylactic oophorectomy is used significantly more frequently than BPM (55% vs. 21%; P < .001). Bilateral prophylactic oophorectomy was more common among women age >= 40 years compared with women aged < 40 years (68% vs. 43%; P < .001) and among porous women compared with nulliparous women (60% vs. 39%; P < .001). There was no difference in BPM (P = .83) or BPO (P = .09) in BRCA1 versus BRCA2 carriers. Multivariate models identified age and parity as a predictor of BPO in BRCA1 carriers; age and ovarian cancer family history in BRCA2 carriers; parity and ovarian cancer family history as a predictor of BPM in BRCA1 carriers; and smoking and ovarian cancer family history in BRCA2 carriers. Conclusion: Bilateral prophylactic oophorectomy is more commonly used than BPM in unaffected BRCA1/2 mutation carriers. Parity, age, and family history can also influence BPO and BPM uptake. Consistent with current recommendations, BPO is used by the majority of porous women aged > 40 years.

Previously, an analysis of 14 extended, high-risk Utah pedigrees localized in the chromosome 22q linkage region to 3.2 Mb at 22q12.3-13.1 (flanked on each side by three recombinants) contained 31 annotated genes. In this large, multi-centered, collaborative study, we performed statistical recombinant mapping in 54 pedigrees selected to be informative for recombinant mapping from nine member groups of the International Consortium for Prostate Cancer Genetics (ICPCG). These 54 pedigrees included the 14 extended pedigrees from Utah and 40 pedigrees from eight other ICPCG member groups. The additional 40 pedigrees were selected from a total pool of 1213 such that each pedigree was required to contain both at least four prostate cancer (PRCA) cases and exhibit evidence for linkage to the chromosome 22q region. The recombinant events in these 40 independent pedigrees confirmed the previously proposed region. Further, when all 54 pedigrees were considered, the three-recombinant consensus region was narrowed down by more than a megabase to 2.2 Mb at chromosome 22q12.3 flanked by D22S281 and D22S683. This narrower region eliminated 20 annotated genes from that previously proposed, leaving only 11 genes. This region at 22q12.3 is the most consistently identified and smallest linkage region for PRCA. This collaborative study by the ICPCG illustrates the value of consortium efforts and the continued utility of linkage analysis using informative pedigrees to localize genes for complex diseases.

Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome families contain germ-line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patient's tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these clinical, radiographic, and molecular markers may prove useful in guiding future application of p53 tumor suppressor therapy.

When a gene mutation is identified in a research study following the death of the study participant, it is not clear whether such information should be made available to relatives. We report here an evaluation of the impact on relatives of being informed of study results that detected pathogenic BRCA2 mutations in a male relative, now deceased, who had early onset (under the age of 55) prostate cancer. The breast and ovarian cancer risk was unknown to the living relatives. Qualitative analysis of interviews with thirteen relatives indicated that those who had a higher risk perception, resulting from an awareness of cancer family history or experiential knowledge of cancer in their family, tended to adjust more easily to the results. All participants believed that genetics research results of clinical significance should be fed back to relatives. Those who were fully aware of the BRCA2 results and implications for themselves felt they had benefited from the information, irrespective of whether or not they had elected for genetic testing, because of the consequent availability of surveillance programs. Initial anxiety upon learning about the BRCA2 result was alleviated by genetic counselling. Factors influencing those who have not engaged with the information included scepticism related to the relative who attempted to inform them, young age and fear of cancer. Those who had not sought genetic counselling did not attempt further dissemination, and some were not undergoing regular screening. Implications for informed consent in genetics research programs, and the requirement for genetic counselling when research results are disclosed, are discussed.

Sweat-gland tumours (SGTs) are uncommon, but malignant varieties are very rare. We have added our data on 30 new cases seen at the Royal Marsden NHS Foundation Trust to the published literature, particularly concentrating on clinical issues. We include a literature review.

Female BRCA gene mutation carriers are at increased risk for developing breast cancer. Ductal lavage is a novel method for sampling breast ductal fluid, providing epithelial cells for cytologic assessment and a source of free DNA for molecular analyses. Loss of heterozygosity (LOH) at the BRCA loci in ductal lavage fluid is a potential biomarker of breast cancer risk. The LOH rate was measured at the BRCA1/2 loci and compared with that at a control locus (APC) using free DNA from the ductal lavage fluid of BRCA carriers and predictive test negative controls. We evaluated the reproducibility of these analyses. Free DNA sufficient for PCR amplification was obtained from 33 ductal lavage samples of 17 healthy women of known BRCA status (14 BRCA carriers and 3 controls). LOH rates of 36.4% to 56.3% at the BRCA1 locus and 45% to 61.5% at the BRCA2 locus were found among BRCA carriers. The LOH rate at the APC locus was lower (18.5%). The interaliquot reproducibility for the D17S855 marker of the BRCA1 locus was 66.7%. Intraaliquot reproducibility was 90%. Although we successfully isolated sufficient free DNA from ductal lavage fluid for PCR amplification, the degree of reproducibility of these LOH studies raises questions about the robustness of this technique as a risk assessment tool in the evaluation of high-risk women. Further studies are required to evaluate the specificity and predictive value of LOH in ductal lavage fluid for breast cancer development.

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.

Purpose: To evaluate acute toxicity induced by chemotherapy for breast cancer in a retrospective study of 62 BRCA1/2 mutation carriers matched 1:1 with women who had treatment for sporadic disease in the United Kingdom between 1983 and 2003.Experimental Design: All participants were interviewed by one of two researchers using Standardized questionnaires, and their medical records were reviewed by one research nurse. The two main regimens received were cyclophosphamide, methotrexate, and fluorouracil and fluorouracil, epirubicin, and cyclophosphamide. The proportion of cases and controls receiving anthracycline-based treatment was equivalent; but fewer BRCA1 cases received this treatment than did BRCA2 mutation carriers. Toxicity was documented using the Eastern Cooperative Oncology Group Common Toxicity Criteria for hematologic, infective, and gastrointestinal toxicities. No increase in toxicity was seen in BRCA1/2 mutation carriers.Results: The only significant difference was that neutropenia was less evident in BRCA2 mutation carriers than in either BRCA1 mutation carriers or controls. As a result, there was no requirement for dose reduction among BRCA2 mutation carriers, in contrast to 10 of 39 BRCA1 carriers and 16 of 62 controls (P = 0.02).Conclusions: This result has implications for therapy and indicates that women with mutations in BRCA1 and BRCA2 may be given the same doses of chemotherapy as noncarriers.

Purpose: To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom.Experimental Design: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points.Results: No increase in clinically significant late toxicity was seen in the mutation carriers.Conclusions: These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.

Germ line mutations in CHEK2, the gene that encodes the Chk2 serine/threonine kinase activated in response to DNA damage, have been found to confer an increased risk of some cancers. We have previously reported the presence of the common deleterious 1100delC and four rare CHEK2 mutations in inherited breast cancer. Here, we report that predictions made by bioinformatic analysis on the rare mutations indicate that two of these, delE161 (483-485delAGA) and R117G, are likely to be deleterious. We show that the proteins encoded by 1100delC and delE161 are both unstable and inefficiently phosphorylated at Thr68 in response to DNA damage, a step necessary for the oligomerization of Chk2. Oligomerization is in turn necessary for additional phosphorylation and full activation of the protein. A second rare mutation, R117G, is phosphorylated at Thr68 but fails to show a mobility shift on DNA damage, suggesting that it fails to become further phosphorylated and hence fully activated. Our results indicate that delE161 and R117G encode nonfunctional proteins and are therefore likely to be pathogenic. The findings from the biochemical analysis correlate well with predictions made by bioinformatics analysis. In addition, the results imply that these mutations, as well as 1100delC, cannot act in a dominant-negative manner to cause cancer, and tumorigenesis in association with these mutations may be due to haploinsufficiency.

In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells.

The value of special screening for women at moderate breast cancer risk with a family history of breast cancer remains controversial. Little is known about recall rates, false negative outcomes and the impact on clinical service. Despite this, surveillance programmes within breast units have been established in the United Kingdom.

The feasibility of a population-based evaluation of screening for prostate cancer in men with a raised familial risk was investigated by studying reasons for non-participation and uptake rates according to postal recruitment and clinic contact. The levels of prostate-specific antigen (PSA) and the positive predictive values (PPV) for cancer in men referred with a raised PSA and in those biopsied were analysed. First-degree male relatives (FDRs) were identified through index cases (ICs): patients living in two regions of England and diagnosed with prostate cancer at age < or =65 years from 1998 to 2004. First-degree relatives were eligible if they were aged 45-69 years, living in the UK and had no prior diagnosis of prostate cancer. Postal recruitment was low (45 of 1687 ICs agreed to their FDR being contacted: 2.7%) but this was partly due to ICs not having eligible FDRs. A third of ICs in clinic had eligible FDRs and 49% (192 out of 389) agreed to their FDR(s) being contacted. Of 220 eligible FDRs who initially consented, 170 (77.3%) had a new PSA test taken and 32 (14.5%) provided a previous PSA result. Among the 170 PSA tests, 10% (17) were > or =4 ng ml(-1) and 13.5% (23) tests above the age-related cutoffs. In 21 men referred, five were diagnosed with prostate cancer (PPV 24%; 95% CI 8, 47). To study further the effects of screening, patients with a raised familial risk should be counselled in clinic about screening of relatives and data routinely recorded so that the effects of screening on high-risk groups can be studied.

This study examined factors that predict psychological morbidity and screening adherence in first-degree relatives (FDRs) taking part in a familial PSA screening study. Prostate cancer patients (index cases - ICs) who gave consent for their FDRs to be contacted for a familial PSA screening study to contact their FDRs were also asked permission to invite these FDRs into a linked psychosocial study. Participants were assessed on measures of psychological morbidity (including the General Health Questionnaire; Cancer Worry Scale; Health Anxiety Questionnaire; Impact of Events Scale); and perceived benefits and barriers, knowledge; perceived risk/susceptibility; family history; and socio-demographics. Of 255 ICs, 155 (61%) consented to their FDRs being contacted. Of 207 FDRs approached, 128 (62%) consented and completed questionnaires. Multivariate logistic regression revealed that health anxiety, perceived risk and subjective stress predicted higher cancer worry (P = 0.05). Measures of psychological morbidity did not predict screening adherence. Only past screening behaviour reliably predicted adherence to familial screening (P = 0.05). First-degree relatives entering the linked familial PSA screening programme do not, in general, have high levels of psychological morbidity. However, a small number of men exhibited psychological distress.

Deleterious mutations in the BRCA1 gene predispose women to an increased risk of breast and ovarian cancer. Many functional studies have suggested that BRCA1 has a role in DNA damage repair and failure in the DNA damage response pathway often leads to the accumulation of chromosomal aberrations. Here, we have compared normal lymphocytes with those heterozygous for a BRCA1 mutation. Short-term cultures were irradiated (8Gy) using a high dose rate and subsequently metaphases were analysed by 24-colour chromosome painting (M-FISH). We scored the chromosomal rearrangements in the metaphases from five BRCA1 mutation carriers and from five noncarrier control samples 6 days after irradiation. A significantly higher level of chromosomal damage was detected in the lymphocytes heterozygous for BRCA1 mutations compared with normal controls; the average number of aberrations per mitosis was 3.48 compared with 1.62 in controls (P=0.0001). This provides new evidence that heterozygous mutation carriers have a different response to DNA damage compared with noncarriers and that BRCA1 has a role in DNA damage surveillance. Our finding has implications for treatment and screening of BRCA1 mutation carriers using modalities that involve irradiation.

The CHEK2 1100delC protein-truncating mutation has a carrier frequency of similar to 0.7% in Northern and Western European populations and confers an similar to 2-fold increased risk of breast cancer. It has also been suggested to increase risks of colorectal and prostate cancer, but its involvement with these or other types of cancer has not been confirmed. The incidence of cancer other than breast cancer in 11,116 individuals from 734 non-BRCA1/2 breast cancer families from the United Kingdom, Germany, Netherlands, and the United States was compared with that predicted by population rates. Relative risks (RR) to carriers and noncarriers were estimated by maximum likelihood, via the expectation-maximization algorithm to allow for unknown genotypes. Sixty-seven families contained at least one tested CHEK2 1100delC mutation carrier. There was evidence of underreporting of cancers in male relatives (422 cancers observed, 860 expected) but not in females (322 observed, 335 expected); hence, we focused on cancer risks in female carriers. The risk of cancers other than breast cancer in female carriers was not significantly elevated, although a modest increase in risk could not be excluded (RR, 1.18; 95% confidence interval, 0.64-2.17). The carrier risk was not significantly raised for any individual cancer site, including colorectal cancer (RR, 1.60; 95% confidence interval, 0.54-4.71). However, between ages 20 to 50 years, the risks of colorectal and lung cancer were both higher in female carriers than noncarriers (P = 0.041 and 0.0001, respectively). There was no evidence of a higher prostate cancer risk in carriers than noncarriers (P = 0.26), although underreporting of male cancers limited our power to detect such a difference. Our results suggest that the risk of cancer associated with CHEK2 1100delC mutations is restricted to breast cancer, although we cannot rule out a small increase in overall cancer risk.

Contrast enhanced magnetic resonance imaging (CE MRI) is the most sensitive tool for screening women who are at high familial risk of breast cancer. Our aim in this study was to assess the cost-effectiveness of X-ray mammography (XRM), CE MRI or both strategies combined. In total, 649 women were enrolled in the MARIBS study and screened with both CE MRI and mammography resulting in 1881 screens and 1-7 individual annual screening events. Women aged 35-49 years at high risk of breast cancer, either because they have a strong family history of breast cancer or are tested carriers of a BRCA1, BRCA2 or TP53 mutation or are at a 50% risk of having inherited such a mutation, were recruited from 22 centres and offered annual MRI and XRM for between 2 and 7 years. Information on the number and type of further investigations was collected and specifically calculated unit costs were used to calculate the incremental cost per cancer detected. The numbers of cancer detected was 13 for mammography, 27 for CE MRI and 33 for mammography and CE MRI combined. In the subgroup of BRCA1 (BRCA2) mutation carriers or of women having a first degree relative with a mutation in BRCA1 (BRCA2) corresponding numbers were 3 (6), 12 (7) and 12 (11), respectively. For all women, the incremental cost per cancer detected with CE MRI and mammography combined was 28 pound 284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to 11 pound 731 (CE MRI vs mammography) and 15 pound 302 (CE MRI and mammography vs mammography). Results were most sensitive to the unit cost estimate for a CE MRI screening test. Contrast-enhanced MRI might be a cost-effective screening modality for women at high risk, particularly for the BRCA1 and BRCA2 subgroups. Further work is needed to assess the impact of screening on mortality and health-related quality of life.

High breast density as measured on mammograms is a strong risk factor for breast cancer in the general population, but its effect in carriers of germline BRCA1 and BRCA2 mutations is unclear. We obtained mammograms from 206 female carriers of BRCA1 or BRCA2 mutations, 96 of whom were subsequently diagnosed with breast cancer and 136 relatives of carriers who were themselves noncarriers. We compared the mammographic densities of affected carriers (cases) and unaffected carriers (controls), and of mutation carriers and noncarriers, using a computer-assisted method of measurement and visual assessment by two observers. Analyses were adjusted for age, parity, body mass index, menopausal status, and hormone replacement therapy use. There was no difference in the mean percent density between noncarriers and carriers. Among carriers, increasing mammographic density was associated with an increased risk of breast cancer (P(trend) = 0.024). The odds ratio (OR; 95% confidence interval) for breast cancer associated with a density of > or =50% was 2.29 (1.23-4.26; P = 0.009). The OR did not differ between BRCA1 and BRCA2 carriers or between premenopausal and postmenopausal carriers. The results suggest that the distribution of breast density in BRCA1 and BRCA2 carriers is similar to that in non-carriers. High breast density in carriers is associated with an increased risk of breast cancer, with the relative risk being similar to that observed in the general population. Use of mammographic density could improve individual risk prediction in carriers.

Cancer genetics is becoming increasingly integrated into oncological care; particularly in breast cancer management. The recognition of monogenic breast cancer predisposition syndromes, such as BRCA, is critical as there is also a risk of other cancers in addition to a markedly elevated risk of contralateral breast cancer. In individuals with breast cancer due to some predisposition genes, radiation should be avoided, e.g. the ATM and TP53 genes, but there is still controversy as to whether radiation should be used in BRCA1/2 mutation carriers and more follow-up is needed. There are some radiation-sensitive genetic conditions where, if breast cancer occurs (as it may occur in any individual, not necessarily due to an increased risk associated with the condition), radiation should be avoided. These conditions are often associated with dysmorphic features. If such features are noticed then the advice of a geneticist should be sought urgently prior to giving radiation.

Men and women who have a family history of breast and/or ovarian cancer may be offered a predictive genetic test to determine whether or not they carry the family specific BRCA1/2 mutation. The sons and daughters of mutation carriers have a 50 per cent chance of inheriting a mutation, which will increase their risk of developing cancer. Little is known about at-risk men's feelings about the part they play in the transmission of BRCA1/2 mutations within their families. This study investigated high risk men's responses to BRCA1/2 predictive genetic testing. Seventeen in-depth interviews were undertaken with carrier (n = 5) and non-carrier men (n = 12). All men described genetic testing as a familial duty. It is observed that carriers and non-carriers mobilised differing explanations about their role in the aetiology of risk. It is noted that men engage in a form of narrative reconstruction in which they draw upon discourses of guilt and blame or fate and predestiny in an effort to present themselves as morally responsible or blameless. It is argued that narrative reconstruction enables these men to reconcile their genetic identity, self and family.

Background Bilateral prophylactic salpingo-cophorectomy (BPSO) is used widely used to reduce the risk of breast and ovarian cancer in women with BRCA1 and BRCA2 mutations. However, the reduction in mortality after this surgery is unclear. We aimed to assess whether BPSO improves overall mortality or cancer-specific mortality in BRCA1 and BRCA2 mutation carriers.Methods We identified a prospective cohort of 666 women with disease-associated gem-dine mutations in BRCA1 or BRCA2 and no previous cancer diagnosis. in our primary analysis, we compared 155 women who had had BPSO and 271 women matched for age at BPSO who had not had BPSO. In our secondary analysis, we compared 188 women who had had BPSO with 478 women who had not. In both analyses, we compared overall mortality and cancer-specific mortality. All analyses were adjusted for Centre, mutation (BRCA1 vs BRCA2), and birth year.Findings In the primary analysis, mean follow-up from BPSO to censoring was 3.1 years [SD 2(.)4] in the BPSO group and 2(.)1 years [2(.)0] in the non-BPSO group. The hazard ratio (HR) for overall mortality was 0(.)24 (95% CI 0(.)08-0(.)71), for breast-cancer-specific mortality was 0(.)10(0(.)02-0(.)71), and for ovarian-cancer-specific mortality was 0(.)05 (0(.)01-0(.)46) for women who had BPSO compared with those who had not. In secondary analysis, BPSO was associated with reduced overall mortality (HR 0(.)28 [95% Cl 0(.)10-0(.)74]), but not with breast-cancer-specific mortality (0(.)15 [0-02-1-18] or ovarian-cancer-specific mortality (0(.)23 [0(.)02-1(.)87]. When regarded as a time-dependent covariate, BPSO was not associated significantly with mortality.Interpretation if confirmed, the finding that BPSO improves overall survival and cancer-specific survival in women with BRCA mutations will complement our existing knowledge of cancer-risk reduction associated with BPSO. Together, these data could give information to women who are considering genetic testing.

We investigated the association between seven polymorphisms in four candidate genes involved in vitamin D and androgen metabolism with early-onset prostate cancer (CaP) risk. The polymorphisms were genotyped in 288 UK males who were diagnosed with CaP at the age of 55 y or younger and up to 700 population-based controls. An additional 50 cases (not selected for age) and 76 controls were also genotyped. Short (< or =22 repeats) AR (CAG)(n) repeats were associated with a significantly reduced risk of early onset CaP (OR 0.68, 95% CI 0.50-0.91) compared with men with long (> 22) repeats. Men homozygous for the leucine variant of SRD5A2 p.89V > L were also found to be at a significantly increased risk of CaP compared with men who were homozygous for the valine allele (OR 1.84, 95% CI 1.15-2.98). No associations were found with the AR (GGC)(n), CYP17 Msp A1 I, VDR Taq I, SRD5A2 (TA)(n) and p.49A >T polymorphisms and CaP risk. These findings suggest that common polymorphisms in the AR and SRD5A2 genes may be associated with early-onset CaP in British men.

Variants in the gene encoding the macrophage scavenger receptor 1 (MSR1(4)) protein have been identified in men with prostate cancer, and several small studies have suggested that the 999C>T (R293X) protein-truncating mutation may be associated with an increased risk for this disease.

To develop a method of processing non-formalin fixed prostate specimens removed at radical prostatectomy to obtain fresh tissue for research and for correlating diagnostic and molecular results with preoperative imaging.

Women genetically predisposed to breast cancer often develop the disease at a young age when dense breast tissue reduces the sensitivity of X-ray mammography. Our aim was, therefore, to compare contrast enhanced magnetic resonance imaging (CE MRI) with mammography for screening.

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

This report outlines a case of Gorlin syndrome, the diagnosis of which was delayed for many years, and raises a number of important issues. These are the spectrum of late radiotherapy effects, particularly after treatment for benign disease, and the importance of considering the possibility of the presence of a genetic syndrome predisposing to cancer in all individuals before starting any treatment. As our knowledge of genetic syndromes expands, this will become increasingly important. Finally, if a genetic predisposition to cancer is suspected, consideration should be given to obtaining a blood sample from the affected patient for DNA storage, particularly if their prognosis is limited. Currently, genetic testing can only be instituted in most families by first obtaining DNA from an individual affected by cancer, as most genetic mutations are unique to a family. If all relatives with cancer have died, then, at this time, genetic testing cannot usually be attempted, unless such samples have previously been stored.

Needle biopsies are taken as standard diagnostic specimens for many cancers, but no technique exists for the high-throughput analysis of multiple individual immunohistochemical (IHC) markers using these samples. Here we present a simple and highly reliable technique for constructing tissue microarrays (TMAs) from prostatic needle biopsies. Serial sectioning of the TMAs, called 'Checkerboard TMAs', facilitated expression analysis of multiple proteins using IHC markers. In total, 100% of the analysed biopsies within the TMA both preserved their antigenicity and maintained their morphology. Checkerboard TMAs will allow the use of needle biopsies (i) alongside other tissue specimens (trans-urethral resection of prostates and prostatectomies in the case of prostate cancer) in clinical correlation studies when searching for new prognostic markers, and (ii) in a diagnostic context for assessing expression of multiple proteins in cancers from patients prior to treatment.

The aim of the current study was to determine the utility of routine digital rectal examination (DRE) after radical radiotherapy for prostate cancer.

To describe the preliminary clinical outcomes of active surveillance (AS), a new strategy aiming to individualize the management of early prostate cancer by selecting only those men with significant cancers for curative therapy, and illustrate the contrast with a policy of watchful waiting (WW).

Radical radiotherapy is a standard form of management of localised prostate cancer. Conformal treatment planning spares adjacent normal tissues reducing treatment-related side effects and may permit safe dose escalation. We have tested the effects on tumour control and side effects of escalating radiotherapy dose and investigated the appropriate target volume margin. After an initial 3-6 month period of androgen suppression, 126 men were randomised and treated with radiotherapy using a 2 by 2 factorial trial design. The initial radiotherapy tumour target volume included the prostate and base of seminal vesicles (SV) or complete SV depending on SV involvement risk. Treatments were randomised to deliver a dose of 64 Gy with either a 1.0 or 1.5 cm margin around the tumour volume (1.0 and 1.5 cm margin groups) and also to treat either with or without a 10 Gy boost to the prostate alone with no additional margin (64 and 74 Gy groups). Tumour control was monitored by prostate-specific antigen (PSA) testing and clinical examination with additional tests as appropriate. Acute and late side effects of treatment were measured using the Radiation Treatment and Oncology Groups (RTOG) and LENT SOM systems. The results showed that freedom from PSA failure was higher in the 74 Gy group compared to the 64 Gy group, but this did not reach conventional levels of statistical significance with 5-year actuarial control rates of 71% (95% CI 58-81%) in the 74 Gy group vs 59% (95% CI 45-70%) in the 64 Gy group. There were 23 failures in the 74 Gy group and 33 in the 64 Gy group (Hazard ratio 0.64, 95% CI 0.38-1.10, P=0.10). No difference in disease control was seen between the 1.0 and 1.5 cm margin groups (5-year actuarial control rates 67%, 95% CI 53-77% vs 63%, 95% CI 50-74%) with 28 events in each group (Hazard ratio 0.97, 95% CI 0.50-1.86, P=0.94). Acute side effects were generally mild and 18 weeks after treatment, only four and five of the 126 men had persistent > or =Grade 1 bowel or bladder side effects, respectively. Statistically significant increases in acute bladder side effects were seen after treatment in the men receiving 74 Gy (P=0.006), and increases in both acute bowel side effects during treatment (P=0.05) and acute bladder sequelae (P=0.002) were recorded for men in the 1.5 cm margin group. While statistically significant, these differences were of short duration and of doubtful clinical importance. Late bowel side effects (RTOG> or =2) were seen more commonly in the 74 Gy and 1.5 cm margin groups (P=0.02 and P=0.05, respectively) in the first 2 years after randomisation. Similar results were found using the LENT SOM assessments. No significant differences in late bladder side effects were seen between the randomised groups using the RTOG scoring system. Using the LENT SOM instrument, a higher proportion of men treated in the 74 Gy group had Grade > or =3 urinary frequency at 6 and 12 months. Compared to baseline scores, bladder symptoms improved after 6 months or more follow-up in all groups. Sexual function deteriorated after treatment with the number of men reporting some sexual dysfunction (Grade> or =1) increasing from 38% at baseline to 66% at 6 months and 1 year and 81% by year 5. However, no consistent differences were seen between the randomised groups. In conclusion, dose escalation from 64 to 74 Gy using conformal radiotherapy may improve long-term PSA control, but a treatment margin of 1.5 cm is unnecessary and is associated with increased acute bowel and bladder reactions and more late rectal side effects. Data from this randomised pilot study informed the Data Monitoring Committee of the Medical Research Council RT 01 Trial and the two studies will be combined in subsequent meta-analysis.

We investigated the association between genetic polymorphisms in GPX1 gene amongst patients who had index squamous cell carcinoma (SCCHN) and a second primary tumour (SPT) after a primary SCCHN in a case-control study. GPX1 genotypes were determined for 61 patients with SPT and for 259 control subjects by a PCR technique using a fluorescent-labelled primer. Analysis was by an ABI automated fluorescent sequencer. The associations between specific genotypes and the development of SPT were examined by logistic regression. A significant difference was found between the control group and the SPT cases in allele frequencies of GPX1 ALA( *)6 and ALA( *)7 (p(trend)=0.04). These results suggest that polymorphisms in the GPX1 gene may be a marker for SPT development and further studies are indicated.

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.

Recent research suggests that women who develop breast cancer between the ages of 30-34 may have specific tumour characteristics: Those with high grade, oestrogen receptor negative, human epidermal growth factor receptor 2 (HER-2) negative tumours have between a 10% and 27% chance of being a BRCA1 gene carrier. Carriers of BRCA1 and BRCA2 mutations have an increased risk of contralateral breast cancer and cancer of the ovary. Furthermore, recent research indicates that prophylactic mastectomy and/or oophorectomy offer a significant risk reduction in the development of breast/ovarian cancer. In the near future, women in the UK may be offered the choice of a genetic test close to the time of diagnosis. This timing not only provides additional dimensions to treatment decisions, but has psycho-social and familial implications as well. This exploratory study investigates, first, whether or not women diagnosed with breast cancer under the age of 40 would want to be offered information about genetic testing close to the time of their diagnosis. Then secondly, it explores whether the health care professionals treating them support this idea. Third, it highlights the reasons for the women and the health professionals perspectives and concerns. We held focus groups of 13 women who had their only, or first, breast cancer under the age of 40 and who were subsequently identified as BRCA1 or BRCA2 mutation carriers, asking them how they felt about this timing. We also interviewed 17 health care professionals involved in various aspect of breast cancer care and cancer genetics. The majority of former breast cancer women and professionals believed that there was already emotional overload in coping with the cancer diagnosis and decisions regarding existing cancer treatment options and that offering genetic testing would add too much additional stress. Some members of both groups, however, thought that offering genetic testing around the time of breast cancer diagnosis would be more important if the results could alter treatment decisions.

Purpose Bilateral prophylactic oophorectomy (BPO) is widely used for cancer risk reduction in women with BRCA1/2 mutations. Many premenopausal women choose to take hormone replacement therapy (HRT) after undergoing BPO to abrogate immediate symptoms of surgically-induced menopause. Thus, we evaluated whether the breast cancer risk reduction conferred by BPO in BRCA1/2 mutation carriers is altered by use of post-BPO HIRT.Methods We identified a prospective cohort of 462 women with disease-associated germline BRCA1/2 mutations at 13 medical centers to evaluate breast cancer risk after BPO with and without HIRT. We determined the incidence of breast cancer in 155 women who had undergone BPO and in 307 women who had not undergone BPO on whom we had complete information on HRT use. Postoperative follow-up was 3.6 years.Results Consistent with previous reports, BPO was significantly associated with breast cancer risk reduction overall (hazard ratio [HR] = 0.40; 95%CI, 0.18 to 0.92). Using mutation carriers without BPO or HRT as the referent group, HRT of any type after BPO did not significantly alter the reduction in breast cancer risk associated with BPO (HR = 0.37; 95% CI, 0.14 to 0.96).Conclusion Short-term HRT use does not negate the protective effect of BPO on subsequent breast cancer risk in BRCA1/2 mutation carriers.

This qualitative interview study explored the way in which information about predictive BRCA1/2 testing and its implications for children is disseminated within the families of at-risk men who undergo genetic testing. Twenty-nine in-depth interviews were carried out with family members [male patients (n = 17), their partners (n = 8) and adult children (n = 4)]. These explored the following themes: experiences of cancer and genetic testing, decision-making about testing and the communication of test results and genetic information within the immediate family. The interviews revealed that both male patients and their partners perceive themselves, rather than health professionals, as responsible for disclosing information about genetic testing and genetic risks to their children. Parents described three different communication strategies for the disclosure of genetic information to their children: complete openness, limited disclosure and total secrecy. The adoption of a particular communication strategy was justified in terms of children's rights to information vs their parental duties to protect their children from anxiety-provoking information. Some of the problems arising from the adoption of different disclosure patterns are identified and the implications for clinical practice are discussed.

Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other factors may modify cancer risk from specific mutations. One possible mechanism is an epigenetic effect of polymorphisms in other genes. Genes involved in hormonal signal transduction are possible candidates. The AIB1 gene, an estrogen receptor (ER) coactivator, is frequently amplified in breast and ovarian tumors. Variation of a CAG repeat length has been reported within this gene that encodes a polyglutamine repeat in the C-terminus of the protein. Three hundred eleven BRCA1/2 mutation carriers (257 were of Ashkenazi origin) were genotyped for the AIB1 polyglutamine repeat. Relative risks (RR) were estimated using a maximum likelihood approach. The estimated breast cancer (BC) RR per average repeat length adjusted for population type (Ashkenazi vs. non-Ashkenazi) was 1.15 (95% CI = 1.02-1.30; p = 0.01) for BRCA1/2 carriers, and 1.25 (95% CI = 1.09-1.42; p = 0.001) when analysis was restricted to BRCA1 carriers. RR of BC was 1.17 (95% CI = 0.91-1.74), for individuals with 2 alleles >/=29 polyglutamine repeats and 0.78 (95% CI = 0.50-1.16) for those with at least 1 allele of </=26 repeats, compared to individuals with the common genotypes 28;28, 28;29 or 28;30. The corresponding BC RR in BRCA1 mutation carriers was 0.55 (95% CI = 0.34-0.90) and 1.29 (95% CI = 0.85-1.96) in those with </=26 and >/=29 repeats respectively (p = 0.025). These results indicate significant association of the risk for BC in carriers of BRCA1 mutations with the polyglutamine chain of the AIB1 gene. Longer repeat length correlates with elevated risk, whereas in carriers of a shorter AIB1 allele BC risk was reduced. The AIB1 polyglutamine length did not affect BC risk among BRCA2 mutation carriers.

It has been postulated that telomere dysfunction and telomerase activation have important roles in prostate tumorigenesis. Since the ataxia-telangiectasia mutated gene product (ATM protein) is involved in maintaining telomere length and integrity, we hypothesized that its expression might be altered in prostate tumors and, thus, examined its profile in 49 tumor samples. The majority (32/49) had ATM protein levels higher than those observed in normal tissues, with only 5 of 49 tissue samples showing reduced or absent ATM levels. Three of these were from the group of 6 young-onset or sibling-pair tumors. There was a trend toward higher ATM expression in tumors with a higher Gleason score (23/32 [72%] for grade 8-10 vs 9/17 [53%] for grades 5-7), although this difference was not statistically significant. These findings support our hypothesis that the presence of the ATM protein at the same or a higher level than that in normal prostate cells might have an important role in the maintenance of the shortened telomeres commonly found in prostate cancer cells.

Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. The RAD51 gene, which participates in homologous recombination double-strand breaks (DSB) repair in the same pathway as the BRCA1 and BRCA2 gene products, is a candidate for such an effect. A single-nucleotide polymorphism (SNP), RAD51-135g-->c, in the 5' untranslated region of the gene has been found to elevate breast cancer (BC) risk among BRCA2 carriers. We genotyped 309 BRCA1/2 mutation carriers, of which 280 were of Ashkenazi origin, 166 noncarrier BC patients and 152 women unaffected with BC (a control group), for the RAD51-135g-->c SNP. Risk analyses were conducted using COX proportional hazard models for the BRCA1/2 carriers and simple logistic regression analysis for the noncarrier case-control population. BRCA2 carriers were also studied using logistic regression and Kaplan-Meier survival analyses. The estimated BC hazard ratio (HR) for RAD51-135c carriers adjusted for origin (Ashkenazi vs non-Ashkenazi) was 1.28 (95% CI 0.85-1.90, P=0.23) for BRCA1/2 carriers, and 2.09 (95% CI 1.04-4.18, P=0.04) when the analysis was restricted to BRCA2 carriers. The median BC age was younger in BCRA2-RAD51-135c carriers (45 (95% CI 36-54) vs 52 years (95% CI 48-56), P=0.05). In a logistic regression analysis, the odds ratio (OR) was 5.49 (95% CI 0.5-58.8, P=0.163). In noncarrier BC cases, carrying RAD51-135c was not associated with BC risk (0.97; 95% CI 0.47-2.00). These results indicate significantly elevated risk for BC in carriers of BRCA2 mutations who also carry a RAD51-135c allele. In BRCA1 carriers and noncarriers, no effect for this SNP was found.

This review describes what is currently known about the genetics of prostate cancer. Traditionally, the genetics of a suspected inherited cancer predisposition have generally been thought of in terms of a single, high-risk gene with a dominant mode of inheritance. Such a gene might be observed in families, as has been documented in familial breast cancer (BRCA1/2), familial colorectal cancer (HNPCC), retinoblastoma (RB1), and Wilms tumor (WT1). This review investigates the evidence for the existence, first of familial prostate cancer, and second, for the presence of such a high-risk gene in those families by epidemiological and experimental approaches. Another current area of interest in prostate cancer is the investigation of the contribution of common lower penetrance genes to the disease. This alternative approach has become popular, as it raises the issue of frequently seen genetic variations such as single nucleotide polymorphisms (SNPs) having relevance to the risk of developing the disease. Finally, this article will explore the way forward, with emphasis on worldwide collaboration from teams attempting to find the genes responsible for the disease and investment in new technologies that will aid in their discovery.

The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G>A (D1853N), 5558A>T (D1853V), ivs38-8t>c and ivs38-15g>c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17-3.87, P=0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C>G variant might be associated with prostate cancer risk.

We have previously shown that the1100delC variant of the cell-cycle-checkpoint kinase gene CHEK2, which is carried by approximately 1% of the population confers a two-fold increase in female breast cancer and a 10-fold increase in male breast cancer. To extend our knowledge on the role of CHEK2 in susceptibility to male breast cancer we have screened a series of 26 breast cancer cases with male representation for germline sequence variation in the CHEK2 gene. One individual was found to harbour the 1100delC variant. No other mutations were identified. Variants other than 1100delC are rare in male breast cancer.

This multi-centre UK study assesses the impact of predictive testing for breast and ovarian cancer predisposition genes (BRCA 1/2) in the clinical context. In the year following predictive testing, 261 adults (59 male) from nine UK genetics centres participated; 9 I gene mutation carriers and 170 noncarriers. Self-report questionnaires were completed at baseline (pre-genetic testing) and 1, 4 and 12 months following the genetic test result. Men were assessed for general mental health (by general health questionnaire (GHQ)) and women for general mental health, cancer-related worry, intrusive and avoidant thoughts, perception of risk and risk management behaviour. Main comparisons were between female carriers and noncarriers on all measures and men and women for general mental health. Female noncarriers benefited psychologically, with significant reductions in cancer-related worry following testing (P<0.001). However, younger female carriers (<50 years) showed a rise in cancer-related worry 1 month post-testing (P<0.05). This returned to pre-testing baseline levels 12 months later, but worry remained significantly higher than noncarriers throughout (P<0.01). There were no significant differences in GHQ scores between males and females (both carriers and noncarriers) at anytime point. Female carriers engaged in significantly more risk management strategies than noncarriers in the year following testing (e.g. mammograms; 92% carriers vs 30% noncarriers). In the 12 months post-testing, 28% carriers had bilateral risk-reducing mastectomy and 31% oophorectomy. Oophorectomy was confined to older (mean 41 yrs) women who already had children. However, worry about cancer was not assuaged by surgery following genetic testing, and this requires further investigation. In all, 20% of female carriers reported insurance problems. The data show persistent worry in younger female gene carriers and confirm changes in risk management consistent with carrier status. Men were not adversely affected by genetic testing in terms of their general mental health.

The impact of the presence of a germ-line BRCA1 mutation on gene expression in normal breast fibroblasts after radiation-induced DNA damage has been investigated.

E2F transcription factors, including EM, directly modulate expression of EZH2. Recently, overexpression of the EZH2 gene has been implicated in the development of human prostate cancer. In tissue microrarray studies we now show that expression of high levels of nuclear E2F3 occurs in a high proportion (98/147, 67%) of human prostate cancers, but is a rare event in non-neoplastic prostatic epithelium suggesting a role for E2F3 overexpression in prostate carcinogenesis. Patients with prostate cancer exhibiting immunohistochemically detectable nuclear E2F3 expression have poorer overall survival (P=0.0022) and cause-specific survival (P=0.0047) than patients without detectable E2F3 expression. When patients are stratified according to the maximum percentage of EM-positive nuclei identified within their prostate cancers (up to 20, 21-40%, etc.), there is an increasingly significant association between E2F3 staining and risk of death both for overall survival (P=0.0014) and for cause-specific survival (P=0.0004). Multivariate analyses select E2F3 expression as an independent factor predicting overall survival (unstratified P=0.0103, stratified P=0.0086) and cause-specific survival (unstratified P=0.0288, stratified P=0.0072). When these results are considered together with published data on EZH2 and on the E2F3 control protein pRB, we conclude that the pRB-E2F3-EZH2 control axis may have a critical role in modulating aggressiveness of individual human prostate cancer.

Previous studies of families with multiple cases of breast cancer have indicated that a frameshift alteration in the CHEK2 gene, 1100delC, is associated with an elevated frequency of breast cancer in such families, but the risk associated with the variant in other situations is uncertain. To evaluate the breast cancer risk associated with this variant, 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in five countries were genotyped. CHEK2*1100delC was found in 201 cases (1.9%) and 64 controls (0.7%) (estimated odds ratio 2.34; 95% CI 1.72-3.20; P=.0000001). There was some evidence of a higher prevalence of CHEK2*1100delC among cases with a first-degree relative affected with breast cancer (odds ratio 1.44; 95% CI 0.93-2.23; P=.10) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis (P=.002). These results confirm that CHEK2*1100delC confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results are consistent with the hypothesis that CHEK2*1100delC multiplies the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer.

BRCA1/2 test decliners/deferrers have received almost no attention in the literature and this is the first study of this population in the United Kingdom. The aim of this multicenter study is to examine the attributes of a group of individuals offered predictive genetic testing for breast/ovarian cancer predisposition who did not wish to proceed with testing at the time of entry into this study. This forms part of a larger study involving 9 U.K. centers investigating the psychosocial impact of predictive genetic testing for BRCA1/2. Cancer worry and reasons for declining or deferring BRCA1/2 predictive genetic testing were evaluated by questionnaire following genetic counseling. A total of 34 individuals declined the offer of predictive genetic testing. Compared to the national cohort of test acceptors, test decliners are significantly younger. Female test decliners have lower levels of cancer worry than female test acceptors. Barriers to testing include apprehension about the result, traveling to the genetics clinic, and taking time away from work/family. Women are more likely than men to worry about receiving less screening if found not to be a carrier. The findings do not indicate that healthy BRCA1/2 test decliners are a more vulnerable group in terms of cancer worry. However, barriers to testing need to be discussed in genetic counseling.

The ductal approach to breast cancer, encompassing nipple aspiration, ductal lavage and duct endoscopy, allows assessment of breast ductal epithelial cells and their local microenvironment in a graded process of increasing invasiveness. Samples of ductal epithelial cells sufficient for cytological diagnosis may be safely collected, titres of individual proteins showing variation with breast cancer status may be measured, and abnormal pathology within the breast ducts may be directly visualized. Identification of surrogate molecular markers may facilitate early breast cancer detection, in conjunction with cytological assessment, and be useful for individual prediction of breast cancer risk and assessment of treatment response. However, the sensitivity and specificity of the ductal approach require further evaluation. The small quantities of nipple aspiration fluid available for analysis, and difficulties identifying and cannulating ducts remain important limitations of these techniques.

This paper highlights the need for carriers to be followed up by health professionals who understand the complexities of the BRCA syndrome. A BRCA carrier clinic has been established in London and regular follow up is an essential part of the care for families. An open door policy has been set up for patients who may meet or telephone the cancer genetic nurse specialist for support and care at any time. An example of the follow up work is discussed in the format of a case of a young woman with a BRCA1 alteration who developed a primary peritoneal cancer following prophylactic oophorectomy. This case illustrates the work of the multi-disciplinary team caring for BRCA carriers.

Differences in reported uptake of genetic testing for mutations in BRCA1 and BRCA2 can largely be accounted for by different methodologies and by studying research vs nonresearch families. In our joint study of 75 nonresearch families from two UK centres in which at least 3 years had elapsed since the initial proband had been informed of the availability of testing, only 45 and 34% of eligible individuals from Manchester and London, respectively, had come forward for counselling. Final uptake rates using a nonproactive approach were 53 and 29% for women and 11-12% for men, but the figure among those attending clinic was 73 and 62%, respectively. Unlike previous studies, we did not find that uptake had stabilised after a year with 25% of those being tested more than 2 years after the family was informed, and several delaying a considerable time between genetics appointments. We believe that the particularly low uptake even of counselling in men may need to be addressed by improving family communication or providing information sheets for family members to disseminate. European Journal of Human Genetics ( 2004).

Health professionals do not inform their patients' kin about BRCA1/2 test results or genetic testing without their written consent. Thus, the onus is on women attending genetic counselling to talk to relatives about the family history and their potential increased risk. This communication process within the family is largely unexplored and provides the focus of the present study. Fifteen healthy women attending a genetics clinic for predictive testing were interviewed prior to receiving their test result and again 6 months later. A grounded theory approach was used. Findings illustrate the dilemmas women faced in juggling social roles and expectations, which had an impact on communication within the family in the context of predictive genetic testing. Tensions between responsibilities towards themselves and others and their fulfilment of social roles had an impact on who women informed and on how they did so. These factors should be considered when assigning patients the role of information provider.

The relationship between risk awareness and anxiety has been the subject of extensive theoretical debate and empirical research. Previous studies of women with a family history of hereditary breast and ovarian cancer suggest that both healthy at-risk women and former cancer patients report increased anxiety upon learning about their increased risks of developing these diseases. Indeed, anxiety about genetic risks has been reported as influencing decisions about DNA-testing and risk-reducing surgery on healthy breasts and ovaries. This qualitative study of women who had been treated for breast/ovarian cancer investigated their perceptions of, and reactions to, their genetic risks of developing further cancers following genetic testing (BRCA1/2 mutation searching). In-depth interviews were undertaken with 30 women (10 mutation carriers, 8 awaiting a result and 12 who received an inconclusive test result). Whilst the majority of women in all three groups adopted a fatalistic approach with regard to their future health and did not regard their genetic risks as a threat to self, a few reported heightened anxiety on learning they were at increased risk of developing a second primary cancer. The data suggest that affected women understand their genetic risks of cancer within the context of their previous disease experiences. It is observed that women's responses to their genetic risk are influenced by the degree to which they have accommodated their risk status in their biography following their diagnosis and treatment of cancer. (C) 2003 Elsevier Ltd. All rights reserved.

This study explores how family communication patterns and family scripts influence the dissemination of genetic information and the sharing of feelings about genetic inheritance in families of healthy women who have attended a cancer genetics risk clinic because of their family history of breast and/or ovarian cancer. Family scripts are sets of expectations, beliefs, and norms that assign meaning to patterns of interaction, connect generations and provide guidance for action. We conducted an exploratory, qualitative study at a major clinical and research cancer center in the United Kingdom from January through June 2000 approved by the hospital clinical research and ethics committees. Twenty-one semi-structured, in-depth interviews were conducted using a purposive sample of women coming to the cancer genetics risk clinic for the first time, supplemented by 5 months of participant observation. We identified several communication patterns: open and supportive; directly blocked, indirectly blocked, self-censored and use of third parties. Some family members shared their feelings and discussed ways of trying to avoid developing breast or ovarian cancer; for others disseminating information or just talking about inherited susceptibility for breast and, or ovarian cancer fell into the script violation category; still others tried to renegotiate their family scripts. Copyright (C) 2003 John Wiley Sons, Ltd.

This paper investigates communication and interactions between healthy women from families with a history of breast/ovarian cancer and five statuses of significant others: (1) women friends; (2) sisters; (3) brothers; (4) male partners; and (5) children in order to better understand the way the family deals with cancer genetics risk information and the extent of social support available to its members. We conducted a research ethics committee reviewed exploratory, qualitative study at a major clinical and research cancer centre in the United Kingdom from January to June 2000. Twenty-one semi-structured, in-depth interviews were conducted using a purposive sample of women coming to the cancer genetics risk clinic for the first time, supplemented by 5 months of participant observation. On the whole, women friends consistently provided strong social support. Sisters were usually close, but communication about the breast/ovarian cancer in their family in some cases was quite limited and fraught with emotional overtones. Brothers were the most difficult to relate to regarding cancer in the family and seemed almost to exist in a different 'interrelational space'. The women claimed that their male partners were supportive, but with caveats. Mothers worried about how much information and at what age they should inform their children about the specifics of the family history of breast/ovarian cancer and tried to protect them when they were young. The women were very concerned about their daughters and granddaughters, but were far less concerned about the impact on their sons.

Prostate cancer is the most common cancer in men and the second highest cause of cancer-related mortality in the U.K. A genetic component in predisposition to prostate cancer has been recognized for decades. One of the strongest epidemiological risk factors for prostate cancer is a positive family history. The hunt for the genes that predispose to prostate cancer in families has been the focus of many research groups worldwide for the past 10 years. Both epidemiological and twin studies support a role for genetic predisposition to prostate cancer. Familial cancer loci have been found, but the genes that cause familial prostate cancer remain largely elusive. Unravelling the genetics of prostate cancer is challenging and is likely to involve the analysis of numerous predisposition genes. Current evidence supports the hypothesis that excess familial risk of prostate cancer could be due to the inheritance of multiple moderate-risk genetic variants. Although research on hereditary prostate cancer has improved our knowledge of the genetic aetiology of the disease, a lot of questions still remain unanswered.This article explores the current evidence that there is a genetic component to the aetiology of prostate cancer and attempts to put into context the diverse findings that have been shown to be possibly associated with the development of hereditary prostate cancer. Linkage searches over the last decade are summarised. It explores issues as to why understanding the genetics of prostate cancer has been so difficult and why despite this, it is still a major focus of research. Finally, current and future management strategies of men with Hereditary Prostate Cancer (HPC) are discussed.

Studies of families with breast cancer have indicated that male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were </=55 years of age. Protein-truncating mutations were found in six men (2.3%; 95% confidence interval 0.8%-5.0%), and all of these mutations were clustered outside the ovarian-cancer cluster region. The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2 mutation was 23-fold. Four of the patients with mutations did not have a family history of breast or ovarian cancer. Twenty-two variants of uncertain significance were also identified. These results confirm that BRCA2 is a high-risk prostate-cancer-susceptibility gene and have potential implications for the management of early-onset prostate cancer, in both patients and their relatives.

We have previously shown that peripheral blood lymphocytes (PBL) from individuals carrying a germline TP53 mutation show a dramatically reduced apoptotic response to radiation. As part of a study of this phenomenon, we also investigated apoptotic response in a series of breast cancer patients lacking TP53 mutations and in a control group of individuals without cancer. There was a significant reduction in mean apoptotic response with increasing age in all groups. These findings are consistent with a number of studies in rodents, which have demonstrated a reduction in DNA damage-induced apoptosis with increasing age. In addition, after adjusting for age, breast cancer patients showed significantly reduced apoptotic responses compared with normal controls (P=0.002). The odds ratio for breast cancer in women with an apoptotic response of <35%, compared with women with a response of >49%, was 6.42 (95% CI 1.68-24.6). The data further support the hypothesis that a reduction in apoptotic response to DNA damage with increasing age may play a significant role in the age-related increase in cancer.

Inherited susceptibility to prostate cancer has been linked to a number of chromosomal regions, however no genes have been unequivocally shown to underlie reported linkages. The putative gene localised to chromosome 1q42-q43, has been designated PCaP. We have recently shown that germline mutations in the fumarate hydratase (FH) gene located on 1q43 cause smooth muscle tumours and renal cell carcinoma. It is conceivable that germline FH mutations might confer an increased risk of prostate cancer and underlie linkage of prostate cancer to PCaP. To examine this proposition we have analysed the entire coding region of FH in 160 prostate cancer cases in 77 multiple case families. No pathogenic mutations in FH were identified in any of the cases. This data makes it highly unlikely that mutations in FH confer susceptibility to prostate cancer.

A database has been created to collect information on families carrying a germ-line mutation in the TP53 gene and on families affected with Li-Fraumeni syndromes [Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL)]. Data from the published literature have been included. The database is available online at http://www.iarc.fr/p53, as part of the IARC TP53 Database. The analysis of the 265 families/individuals that have been included thus far has revealed several new findings. In classical LFS families with a germ-line TP53 mutation (83 families), the mean age of onset of breast cancer was significantly lower than in LFS families (16 families) without a TP53 mutation (34.6 versus 42.5 years; P = 0.0035). In individuals with a TP53 mutation, a correlation between the genotype and phenotype was found. Brain tumors were associated with missense TP53 mutations located in the DNA-binding loop that contact the minor groove of DNA (P = 0.01), whereas adrenal gland carcinomas were associated with missense mutations located in the loops opposing the protein-DNA contact surface (P = 0.003). Finally, mutations likely to result in a null phenotype (absence of the protein or loss of function) were associated with earlier onset brain tumors (P = 0.004). These observations have clinical implications for genetic testing and tumor surveillance in LFS/LFL families.

To report a case-control study examining the relationship between polymorphisms in the leptin receptor (OBR) gene and the development of young-onset prostate cancer, because epidemiological studies report that prostate cancer risk is associated with animal fat intake, and thus we investigated if this association occurs via this genetic mechanism.

While there are numerous uncertainties surrounding prostate cancer's detection and treatment, more research focusing on the psychological needs of prostate patients is required. This study investigated the support and psychological care needs of men with prostate cancer. Patients were approached during urological oncology clinics and asked to complete the: Support Care Needs Survey (SCNS), Support Care Preferences Questionnaire, EORTC QLQ-C30 (Version 3) Measure plus Prostate Module, and the Hospital Anxiety and Depression Scale (HADS). Of the 249 patients meeting study entry criteria, there was an 89% response rate resulting in a cohort of 210 patients. The data showed that significant unmet need exists across a number of domains in the areas of psychological and health system/information. The more commonly reported needs were 'fears about cancer spreading (44%),' 'concerns about the worries of those close to you (43%),' and 'changes in sexual feelings (41%).' Half of all patients reported some need in the domain of sexuality, especially men younger than 65 years. Needs were being well met in the domain of patient care and support. A significant number of patients reported having used or desiring support services, such as information about their illness, brochures about services and benefits for patients with cancer (55%), a series of talks by staff members about aspects of prostate cancer (44%), and one-on-one counselling (48%). Quality of life (QoL) was most negatively impacted in those who: were < or =65 years old, had been diagnosed within one year, or had metastatic disease. Men < or =65 had decreased social functioning, greater pain, increased sleep disturbance, and were more likely to be uncomfortable about being sexually intimate. Patients recently diagnosed had increased fatigue, more frequent urination, greater disturbance of sleep, and were more likely to have hot flushes. Those with advanced disease scored lower on 12 out of 15 QoL categories. PSA level had no effect on QoL or anxiety/depression scores. Men with advanced disease had greater levels of depression and those < or =65 years old were more likely to be anxious. Although most men with prostate cancer seem to function quite well, a substantial minority report areas of unmet need that may be targets for improving care.

BACKGROUND. The aggregation of prostate cancer within families suggests a major inherited component to the disease. Genetic linkage studies have identified several chromosomal regions that may contain prostate cancer susceptibility loci, but none has been definitively implicated.METHODS. We performed a genome-wide linkage search based on 64 families, 63 with at least 3 cases of prostate cancer, ascertained in five countries. The majority of cases from these centers presented with clinically detected disease. Four hundred and one polymorphic markers were typed in 268 individuals. Multipoint heterogeneity analysis was conducted under three models of susceptibility; non-parametric analyses were also performed.RESULTS. Some weak evidence of linkage, under at least one of the genetic models, was observed to markers on chromosomes 2 (heterogeneity LOD (HLOD) = 1.15, P = 0.021), 3 (HLOD = 1.25, P = 0.016), 4 (HLOD = 1.28, P = 0.015), 5 (HLOD = 1.20, P = 0.019), 6 (HLOD = 1.41, P = 0.011), and 11 (HLOD = 1.24, P = 0.018), and in two regions on chromosome 18 (HLOD = 1.40, P = 0.011 and HLOD = 1.34, P = 0.013). There were no HLOD scores greater than 1.5 under any model, and no locus would be predicted to explain more than half of the genetic effect. No evidence in favor of linkage to previously suggested regions on chromosomes 1, 8,17, 20, or X was found.CONCLUSIONS. Genetic susceptibility to prostate cancer is likely to be controlled by many loci, with no single gene explaining a large fraction of the familial risk. Pooling of results from all available genome scans is likely to be required to obtain definitive linkage results.

The practice of medicine will increasingly be medicine of the family rather than the traditional physician/patient dyad, especially where a genetic condition is involved. This study explores how clients from suspected hereditary breast and ovarian cancer (HBOC) families seeking cancer genetics risk counselling are influenced by family stories and the use of heuristics (inferential shortcuts used to make sense of complicated Information) in interpreting and applying genetic information they receive, and suggests ways in which genetic counsellors can Integrate family context into their traditional counselling practices. We conducted an exploratory, qualitative study at a major clinical and research cancer centre in the United Kingdom from January to June 2000 which was reviewed by the hospital clinical research and ethics committees. Twenty-one semi-structured, in-depth interviews were conducted using a purposive sample of women coming to the cancer genetics clinic for the first time, supplemented by five months of clinical observation at weekly clinics. In addition to many family stories based on the number and outcomes of the cancers in their families, we noted: ( 1) fragments of stories, (2) Secret stories, (3) emerging explanations and (4) misconceptions. We did not find widespread intergenerational family myths. The women used three main heuristics in interpreting their breast/ovarian cancer risk: ( 1) representativeness, (2) availability and (3) illusion of control, as well as what Kahneman refers to as the Peak and End rule. Recent psychological research indicates that illusions of control may have positive affects on both physical and mental health. This may pose a future ethical issue for genetic counsellors in determining how to balance the benefit of positive illusions with the delivery of statistical probabilities of risk.

This paper investigates how healthy women with a family history of breast/ovarian cancer live with their heightened awareness of risk, and introduces a chronic risk perspective for studying this topic. Healthy women from these at-risk families and individuals suffering from a chronic illness address many of the same issues concerning adaptation to biographical disruption and an uncertain future. We report on risk perception, family history, life stages, biographical interruptions and the women's attempts to control their risk through a healthy life style and health care beliefs and practices. We conducted an exploratory, qualitative study at a major clinical and research cancer centre in the UK from January - June 2000 that was approved by the hospital clinical research and ethics committees. Twenty-one semi-structured, in-depth interviews were conducted using a purposive sample of women coming to the cancer genetics risk clinic for the first time. We found that the women used various coping strategies in order to 'get on with their lives' - one not dominated by thoughts about long-term risk for cancer. Many women believed that a healthy life style, stress reduction and participating in an annual screening programme for breast/ovarian cancer was the best way to achieve their goal.

Using data obtained during a retrospective interview study of 30 women who had undergone genetic testing - BRCA1/2 mutation searching - this paper describes how women, previously diagnosed with breast/ovarian cancer, perceive their role in generating genetic information about themselves and their families. It observes that when describing their motivations for undergoing DNA testing and their experiences of disclosing genetic information within the family these women provide care based ethical justifications for their actions. Finally, it argues that generating genetic information and disclosing this information to kin raise different types of ethical issues. The implications of these findings for ethical debates about informed choice in the context of genetic testing are discussed.

The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate "BRCA3" locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (alpha) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603-9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (alpha = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at alpha = 0.65 was -11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.

While screening for germline CHK2 mutations in cancer cases by heteroduplex CSGE, we observed that additional PCR fragments were generated from the 3' end region of the gene that includes exons 11-14. Direct sequencing of these fragments suggested that homologous loci (possibly pseudogenes) were concomitantly being amplified. Searches of public sequence databases showed that a number of areas of the genome show a high degree of homology to exons 10-14 of the CHK2 gene. The presence of these homologous regions means that standard screening methods for detecting mutations in CHK2, based on PCR of genomic DNA, are prone to error. To circumvent this problem, we have developed a strategy, based on long-range PCR, to screen the functional copy of CHK2. Using this approach it is possible to carry out a comprehensive mutational analysis of CHK2 from genomic DNA.

Polymorphisms in the promoter regions of cytokine genes may influence prostate cancer (PC) development via regulation of the antitumor immune response and/or pathways of tumor angiogenesis. PC patients (247) and 263 controls were genotyped for interleukin (IL)-1beta-511, IL-8-251, IL-10-1082, tumor necrosis factor-alpha-308, and vascular endothelial growth factor (VEGF)-1154 single nucleotide polymorphisms. Patient control comparisons revealed that IL-8 TT and VEGF AA genotypes were decreased in patients compared with controls [23.9 versus 32.3%; P = 0.04, odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.44-0.99 and 6.3 versus 12.9%; P = 0.01, OR = 0.45, 95% CI 0.24-0.86, respectively], whereas the IL-10 AA genotype was significantly increased in patients compared with controls (31.6 versus 20.6%; P = 0.01, OR = 1.78, 95% CI 1.14-2.77). Stratification according to prognostic indicators showed association between IL-8 genotype and log prostate-specific antigen level (P = 0.05). These results suggest that single nucleotide polymorphisms associated with differential production of IL-8, IL-10, and VEGF are risk factors for PC, possibly acting via their influence on angiogenesis.

The candidate prostate cancer susceptibility gene HPC2/ELAC2 has two common coding polymorphisms: (Ser-->Leu 217) and (Ala-->Thr 541). The Thr541 variant in the HPC2/ELAC2 gene has previously been reported to be at an increased frequency in prostate cancer cases. To evaluate this hypothesis we genotyped 432 prostate cancer patients (including 262 patients diagnosed <or=55 years) and 469 UK, population based control individuals with no family history of cancer. We found no significant difference in the frequencies of Thr541-containing genotypes between cases and controls (OR=1.41, 95% CI 0.79-2.50). The association remained non-significant when the analysis was restricted to cases divided by age of onset into those diagnosed <or=55 years (OR=1.50, 95% CI 0.79-2.85) or to patients diagnosed >55 years (OR=1.27, 95% CI 0.59-2.74). We conclude that any association between the Thr541 variant and prostate cancer is likely to be weak.

We have recently shown that the CHEK2*1100delC mutation acts as a low penetrance breast cancer susceptibility allele. To investigate if other CHEK2 variants confer an increased risk of breast cancer, we have screened an affected individual with breast cancer from 68 breast cancer families. Five of these individuals were found to harbour germline variants in CHEK2. Three carried the 1100delC variant (4%). One of these three individuals also carried the missense variant, Arg180His. In the other two individuals, missense variants, Arg117Gly and Arg137Gln, were identified. These two missense variants reside within the Forkhead-associated domain of CHEK2, which is important for the function of the expressed protein. None of these missense variants were present in 300 healthy controls. Microdissected tumours with a germline mutation showed loss of the mutant allele suggesting a mechanism for tumorigenesis other than a loss of the wild type allele. This study provides further evidence that sequence variation in CHEK2 is associated with an increased risk of breast cancer, and implies that tumorigenesis in association with CHEK2 mutations does not involve loss of the wild type allele.

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS) is in progress. The study design, accrual to date, and related research projects are described. Revised accrual rates and expected recruitment are given. 15 cancers have been detected to date, from a total of 1236 screening measurements. This event rate and the tumour grades reported are compared with recent reports from other studies in women at high risk of breast cancer.

To determine the variability of prostate-specific antigen (PSA) in the breast ductal fluid (nipple aspiration fluid, NAF) during the menstrual cycles of healthy premenopausal women.

Epidemiological studies have suggested an association between low selenium levels and the development of prostate cancer. Human cellular glutathione peroxidase I (hGPX1) is a selenium-dependent enzyme that protects against oxidative damage and its peroxidase activity is a plausible mechanism for cancer prevention by selenium. The GPX1 gene has a GCG repeat polymorphism in exon 1, coding for a polyalanine tract of five to seven alanine residues. To test if the GPX1 GCG repeat polymorphism associates with the risk of young-onset prostate cancer we conducted a case-control study. The GPX1Ala genotypes were determined for 267 prostate cancer cases and 260 control individuals using polymerase chain reaction (PCR) amplification with fluorescently labelled primers and an ABI 377 automated genotyper. Associations between specific genotypes and the risk of prostate cancer were examined by logistic regression. We found no significant association between the GPX1 genotypes and prostate cancer. There was however an increased frequency of the GPX1Ala6/Ala6 genotype in the prostate cancer cases compared to controls (OR: 1.67; 95% CI: 0.97-2.87). The result of this study suggests that the GPX1 genotype is unlikely to be associated with the risk of developing prostate cancer.

Interindividual differences in susceptibility to hematologic malignancies may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs) have been implicated as susceptibility genes in this context for a number of cancers. The aim of this study was to examine whether polymorphic variation in GSTs confers susceptibility to chronic lymphocytic leukemia (CLL). GSTM1, GSTT1, and GSTP1 genotypes were determined in 138 patients and 280 healthy individuals. The frequency of both GSTM1 and GSTT1 null genotypes and the GSTP1-Ile allele was higher in cases than in controls. There was evidence of a trend in increasing risk with the number of putative "high-risk" alleles of the GST family carried (P =.04). The risk of CLL associated with possession of all 3 "high-risk" genotypes was increased 2.8-fold (OR = 2.8, 95% confidence interval: 1.1-6.9). Our findings suggest that heritable GST status may influence the risk of developing CLL.

The aim of this multi-centre UK study is to examine the attributes of a cohort offered predictive genetic testing for breast/ovarian cancer predisposition, Participants are adults unafffected with cancer from families with a known BRCA1/2 mutation. This is the first large multi-centre study of this population in the UK. The study evaluates mental health, perceived risk of developing cancer, preferred risk management options, and motivation for genetic testing. Participants were assessed when coming forward for genetic counselling prior to proceeding to genetic testing. Three hundred and twelve individuals, 76% of whom are female, from nine UK centres participated in the study. There are no gender differences in rates of psychiatric morbidity. Younger women (<50 years) are more worried about developing cancer than older women, Few women provide accurate figures for the population risk of breast (37%) or ovarian (6%) cancer but most think that they are at higher risk of developing breast (88%) and ovarian (69%) cancer than the average woman, Cancer related worry is not associated with perceived risk or uptake of risk management options except breast self-examination, The findings indicate that younger women may be particularly vulnerable at the time of the offer of a predictive genetic test. (C) 2002 Cancer Research UK.

Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer(1), but account for only a small fraction of breast cancer susceptibility(1,2). To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3-5). We show that CHEK2*1100delC, a truncating variant that abrogates the kinase activity(6), has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P=0.00000003), including 13.5% of individuals from families with male breast cancer (P=0.00015). We estimate that the CHEK2*1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.

This study sought to investigate the impact of BRCA1 and BRCA2 mutation searching on women previously diagnosed with breast or ovarian cancer. In-depth interviews were undertaken with 30 women who had undergone a BRCA1 and BRCA2 mutation search within the clinical setting. The main reasons reported for undergoing mutation searching were: to provide genetic information for other family members, general altruism, curiosity about the aetiology of cancer, and to provide information to facilitate risk management decisions. In the main, the process of undergoing genetic testing was not experienced as anxiety provoking. The benefit of receiving a result confirming the presence of a genetic mutation was seen as an end to uncertainty, whereas the costs included difficulties in disclosing information to kin and potentially increased anxiety about one's own or others' cancer risks. Women receiving an inconclusive test result reported a range of emotional reactions. There was evidence that some women misunderstood the meaning of this result, interpreting it as definitive confirmation that a cancer-predisposing mutation was not present within the family. It is concluded that women with cancer who participate in BRCA1 and BRCA2 testing need to receive clear information about the meaning and implications of the different types of test results. Some recommendations for clinical practice are discussed.

The purpose of this study was to explore experiences of cancer in the family and motivation for predictive genetic testing among women at increased risk of developing breast and/or ovarian cancer due to their family history. Fifteen women were interviewed prior to receiving their genetic test results. A grounded theory approach was adopted to analyse the interview transcripts. The findings indicated that experiences of cancer in the family play an important role in formulating beliefs about one's own risk and motivation for predictive genetic testing. A sense of responsibility for one's own health and the need to take action either to prevent cancer or detect cancer at as early a stage as possible, as well as a feeling of responsibility towards children and other family members was apparent. The findings raise the question of whether there is any real choice available to these women and whether there is a negative impact on family dynamics.

Mutations in the tumor suppressor gene TP53 are frequent in most human cancers. Comparison of the mutation patterns in different cancers may reveal clues on the natural history of the disease. Over the past 10 years, several databases of TP53 mutations have been developed. The most extensive of these databases is maintained and developed at the International Agency for Research on Cancer. The database compiles all mutations (somatic and inherited), as well as polymorphisms, that have been reported in the published literature since 1989. The IARC TP53 mutation dataset is the largest dataset available on the variations of any human gene. The database is avail, able at wwwdarc.fr/P53/. In this paper, we describe recent developments of the database. These developments include restructuring of the database, which is now patient-centered, with more detailed annotations on the patient (carcinogen exposure, virus infection, genetic background). In addition, a new on,line application to retrieve somatic mutation data and analyze mutation patterns is now available. We also discuss limitations on the use of the database and provide recommendations to users.

We describe an improved, fast, automated method for screening large genes such as BRCA2 for germline genomic mutations. The method is based on heteroduplex analysis, and has been adapted for a high throughput application by combining the fluorescent technology of automated sequencers and robotic sample handling. This novel approach allows the entire BRCA2 gene to be screened with appropriate overlaps in four lanes of an ABI 377 gel. The method will detect all types of mutations, especially point mutations, more reliably and robustly than other commonly used conformational sensitive methods (e.g. CSGE). In addition we show that this approach, which relies on band shift detection, is able to detect single base substitutions that have hitherto only been detectable by direct sequencing methods.

Cellular characteristics of nipple aspiration fluid during the menstrual cycle in healthy premenopausal women Fifteen healthy premenopausal female volunteers underwent weekly nipple aspiration of ductal fluid from both breasts during two menstrual cycles to investigate the variability of the cellular profile of the ductal fluid. Ductal fluid was successfully obtained using breast massage and nipple-areolar suction from 247/280 (89%) breasts. 83% of samples available for cytological analysis were cellular and 30% of cellular aspirates contained ductal epithelial cells identified using standard morphological criteria. No significant variation in cell number or cell type was identified during the menstrual cycle. All samples tested had an 'H' score of zero for oestrogen receptor. Seven out of 14 women expressed the proliferation marker Mcm-2 in the cells of at least one of the specimens, with no evidence of a menstrual cycle influence on expression. In conclusion, the cellular profile of breast ductal fluid did not vary consistently during the menstrual cycle, permitting future breast cancer screening studies incorporating serial nipple aspirations to be performed independent of the phase of the cycle.

Variation in the penetrance estimates for BRCA1 and BRCA2 mutations carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. A previous study has suggested that BRCA1 carriers with longer lengths of the CAG repeat in the androgen receptor (AR) gene are at increased risk of breast cancer (BC). We genotyped 188 BRCA1/2 carriers (122 affected and 66 unaffected with breast cancer), 158 of them of Ashkenazi origin, 166 BC cases without BRCA1/2 mutations and 156 Ashkenazi control individuals aged over 56 for the AR CAG and GGC repeats. In carriers, risk analyses were conducted using a variant of the log-rank test, assuming two sets of risk estimates in carriers: penetrance estimates based on the Breast Cancer Linkage Consortium (BCLC) studies of multiple case families, and lower estimates as suggested by population-based studies. We found no association of the CAG and GGC repeats with BC risk in either BRCA1/2 carriers or in the general population. Assuming BRCA1/2 penetrance estimates appropriate to the Ashkenazi population, the estimated RR per repeat adjusted for ethnic group (Ashkenazi and non-Ashkenazi) was 1.05 (95%CI 0.97-1.17) for BC and 1.00 (95%CI 0.83-1.20) for ovarian cancer (OC) for CAG repeats and 0.96 (95%CI 0.80-1.15) and 0.90 (95%CI 0.60-1.22) respectively for GGC repeats. The corresponding RR estimates for the unselected case-control series were 1.00 (95%CI 0.91-1.10) for the CAG and 1.05 (95%CI 0.90-1.22) for the GGC repeats. The estimated relative risk of BC in carriers associated with > or =28 CAG repeats was 1.08 (95%CI 0.45-2.61). Furthermore, no significant association was found if attention was restricted to the Ashkenazi carriers, or only to BRCA1 or BRCA2 carriers. We conclude that, in contrast to previous observations, if there is any effect of the AR repeat length on BRCA1 penetrance, it is likely to be weak.

Diagnostic or predictive testing for germline mutations in cancer predisposition genes is inherently slow as result of both genetic counselling and mutation analysis. The overall time taken for mutation testing is not generally perceived as harmful to the individual and may be positively beneficial in order to permit full reflection on the implication of the genetic test results. However, we present three cases where we considered urgent genetic testing for the presence of mutations in th BRCA 1 and 2 genes to be necessary as the test result would have altered the subsequent clinical management of these individuals or their families.

It is not uncommon for cancer geneticists to be referred families with apparently Mendelian co-inheritance of breast and bowel cancer. Such families present a particular problem as regards the intensity of their screening for these diseases and the utility of genetic testing. Many 'breast-colon' cancer families probably result from chance clustering of two common cancers. Other 'breast-colon' cancer families may result from known cancer syndromes, such as hereditary breast-ovarian cancer or hereditary non-polyposis colon cancer, either by conferring a high risk of one cancer type and a slightly increased risk of the other, or through a predisposition to one of the two cancers and chance occurrence of the other. Anecdotally, however, many geneticists wonder about the existence of a distinct 'breast-colon cancer syndrome', since some families present good a priori evidence of genetic disease and yet cannot readily be accounted for by known genes or chance. The identification of unknown 'breast-colon cancer' genes is likely to be difficult, relying primarily on candidate gene analysis, including loci separately implicated in breast or colorectal cancer, or in other multiple cancer syndromes. Studies such as those on APC I1307K and CHEK2 1100delC may suggest the way forward for the identification of 'breast-colon cancer' genes.

There is increasing evidence that predisposition to some cancers has a genetic component. There is a high incidence of loss of heterozygosity on chromosome 9, in the region of tumour suppressor gene, CDKN2A (also known as p16), in sporadic squamous cell cancer of the head and neck (SCCHN). To investigate the possibility that CDKN2A may be involved in the inherited susceptibility to SCCHN, the 3 coding exons of CDKN2A were sequenced in 40 patients who had developed a second primary cancer after an index squamous cell cancer of the head and neck. No mutations were found and we conclude that CDKN2A mutations do not play a major role in cancer susceptibility in this group.

In breast cancer, mutations of predisposition genes such as BRCA-1/2 and other genes as yet uncharacterised are manifest in up to 10% of cases. Although the prior probability of the presence of a breast cancer predisposing gene can be calculated for individual women, there is no published evidence to justify predicted risk as a selection criteria for screening. This study aims to define which patient groups with a significant family history should be screened, and whether clinical examination is necessary in addition to mammography. The Claus model was used to predict breast cancer risk in women with a family history. Women were divided into two groups according to their predicted risk: group I consisted of women at standard risk (lifetime risk less than 1:6) and group II with moderate/high risk (lifetime risk greater than or equal to 1:6). Women were cancer-free at the point of entry, and screening consisted of annual clinical examination and mammography from the age of 35 years. This study consisted of 1500 women in group I and 1078 in group II. The period of observation was 5902.0 and 4327.8 women years, respectively. A total of 31 cancers were detected, 12 in group I and 19 in group II. The median age at diagnosis in group II was 45 years (range 26-66 years) compared with 54.5 years (range 38-63 years) in group I (P=0.03). The relative risk of developing breast cancer in group II was 2.6 (95% confidence interval (CI) 1.2-5.8). When compared with breast cancer incidence in the normal population, the standardised incidence ratio in group II was significantly higher at 2.8 (95% CI: 1.7-4.2). The standardised incidence ratio of women in group I was similar to that of the general population (1.1 (95% CI: 0.6-1.8)). A total of 26/31 (84%) cancers detected were palpable, of which 14 (54%) were not visible on mammography. Approximately one-third of all palpable cancers were detected at routine follow-up. Mammography correctly identified 17/31 cancers (55%), but 29% of these were not palpable. Family history screening programmes are effective and women should be selected for screening according to predicted risk. The younger age of diagnosis in group II justifies screening from an earlier age using both annual clinical examination and mammography.

There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The GSTs have been consistently implicated as cancer susceptibility genes in this context. The GST supergene family includes several loci with well characterized polymorphisms. Approximately 50% of the Caucasian population are homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1, resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an Ile to Val substitution which consequently alters the enzymatic activity of the protein and this has been suggested as a putative high-risk genotype in various cancers. We investigated the relationship between GST polymorphisms and young onset prostate cancer in a case-control study. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate cancer patients and for 280 geographically matched control subjects. We found no significant difference in the frequency of GSTM1 or GSTT1 null genotypes between cases and controls. GSTP1 genotype was, however, significantly associated with prostate cancer risk: the Ile/Ile homozygotes had the lowest risk and there was a trend in increasing the risk with the number of 105 Val alleles: Ile/Val odds ratio (OR)= 1.30 (95% FCI 0.99-1.69), Val/Val OR = 1.80 (95% FCI 1.11-2.91); Ptrend = 0.026. These results suggest that the GSTP1 polymorphism may be a risk factor for developing young onset prostate cancer. We also found that carrying more than one putative high-risk allele in the carcinogen metabolizing GST family was associated with an elevated risk for early onset prostate cancer (OR 2.48, 95% FCI 1.22-5.04, Ptrend = 0.017).

We have tested two rapid assays of p53 function, namely the apoptotic assay and the FASAY as means of detecting germline p53 mutations in members of Li-Fraumeni and Li-Fraumeni-like families. Results of the functional assays have been compared with direct sequencing of all 11 exons of the p53 gene. The results show good agreement between the two functional assays and between them and sequencing. No false-positives or negatives were seen with either functional assay although the apoptotic assay gave one borderline result for an individual without a mutation. As an initial screen the apoptotic assay is not only rapid but inexpensive and very simple to perform. It would be expected to detect any germline defect that leads to loss of p53 function. The apoptotic assay could be ideal as a means of prescreening large numbers of samples and identifying those that require further investigation. The FASAY detects mutations in exons 4-10, is rapid and distinguishes between functionally important and silent mutations.

Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was < or = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (< or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation.

BRCA1 and BRCA2 breast cancer predisposition gene mutation carriers are at markedly increased risk of breast and other cancers. The consideration of chemopreventative options will depend on the cancer site and age-specific penetrance curve. Most chemoprevention studies to date have investigated the role of endocrine intervention in women at increased risk of breast cancer, and study results are conflicting. At the present time, there is uncertainty regarding whether endocrine intervention, particularly with tamoxifen, is as effective in BRCA1 and BRCA2 mutation carriers as in other women who are at increased risk of breast cancer because of hormonal factors or genes with moderately conferred cancer risks. Furthermore, if chemoprevention were needed for at least 10 years to produce an effect, new chemoprevention agents will need to be developed for women in their 30s, as the breast cancer risk curves are steepest between 40 and 50 years of age. Consideration is now being given to types of chemoprevention in this younger age group. There is also an increased risk of other cancers (in particular ovarian cancer and, in men, prostate cancer), and considerations regarding chemoprevention will have to encompass cancer at these sites.

To assess several molecular markers (detected by immunohistochemistry, IHC) to determine whether they can be used to improve the prognostic value of histological grade alone in predicting the behaviour of prostate cancer.

The development of intervention strategies for carriers of mutations in the BRCA1 and BRCA2 genes has several considerations. The first are primary prevention and secondary prevention in unaffected carriers using medical/surgical or lifestyle strategies to prevent cancer development, or screening methods to detect cancers at an earlier stage. The options available are determined by the magnitude and age at onset, risk profile of cancer in carriers (the penetrance function of the gene) and the different cancer sites involved. The management of affected individuals who are BRCA1 and BRCA2 mutation carriers may be altered by their carrier status, because the tumour histology, efficacy of treatment and risk of subsequent cancer development is determined by the BRCA1 and BRCA2 germline status. Carriers of BRCA1 and BRCA2 mutations are relatively rare, so the strategies for management should be determined by international multicentre studies.

There is evidence for genetic predisposition to prostate cancer. However, prostate cancer genes have been more difficult to find than genes for some of the other common cancers, such as breast and colon cancer. The reasons for this are discussed in this article and it is now becoming clear that prostate cancer is probably due to multiple genes, many of which are moderate or low penetrance. The advances in the Human Genome Project and technology, especially that of robotics, will help to overcome these problems. Prostate Cancer and Prostatic Diseases (2000) 3, 241-247

In 1994, the UK National Health Service identified as a research priority that magnetic resonance imaging (MRI) should be assessed as a screening tool for young, pre-menopausal women who are at a high genetic risk of developing breast cancer. In 1997 a national multicentre study was established to compare MRI with X-ray mammography as a method for screening for breast cancer in this group of women. This paper reviews the relevant literature and describes the rationale that led to the setting up of this study.

The protocol of the national multicentre study of Magnetic Resonance Imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The sensitivity and specificity of contrast-enhanced MRI will be compared with two-view X-ray mammography in a comparative trial. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for 3 years, with annual MRI and X-ray examination continuing for up to 5 years. A symptomatic cohort will be measured in the initial phase of the study to ensure consistent reporting between centres. The MRI examination will comprise an initial high-sensitivity screening measurement, followed by a high-specificity measurement in equivocal cases. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. The psychological impact of screening in this high-risk group will be ascertained.

We report the case history of a woman with a germ line mutation in the TP53 gene who developed 17 separate primary tumours. The incidence of new tumours rose steeply after adjuvant tamoxifen treatment for breast cancer and adjuvant vaginal vault radiotherapy for endometrial cancer. This increase could be due to cumulative genetic damage from environmental agents and the fact that the patient lived to the relatively late age of 60 years, or to a high inherent deleterious somatic mutation rate, which could represent the inability of cells from patients with TP53 mutations to repair therapy-induced genetic damage.

We present the case histories of Ashkenazi Jewish twins of opposite sex who developed breast cancer simultaneously, in whom testing for the anticipated BRCA2 mutations was unexpectedly negative. Their management and the implications of this difficult situation are discussed.

We ascertained 184 Ashkenazi Jewish women with breast/ovarian cancer (171 breast and 13 ovarian cancers, two of the former also had ovarian cancer) in a self-referral study. They were tested for germline founder mutations in BRCA1 (185delAG, 5382insC, 188del11) and BRCA2 (6174delT). Personal/family histories were correlated with mutation status. Logistic regression was used to develop a model to predict those breast cancer cases likely to be germline BRCA1/BRCA2 mutation carriers in this population. The most important factors were age at diagnosis, personal/family history of ovarian cancer, or breast cancer diagnosed before 60 years in a first degree relative. A total of 15.8% of breast cancer cases, one of 13 ovarian cancer cases (7.7%), and both cases with ovarian and breast cancer carried one of the founder mutations. Age at diagnosis in carriers (44.6 years) was significantly lower than in non-carriers (52.1 years) (p<0.001), and was slightly lower in BRCA1 than BRCA2 carriers. Thirty three percent of carriers had no family history of breast or ovarian cancer in first or second degree relatives. Conversely, 12% of non-mutation carriers had strong family histories, with both a first and a second degree relative diagnosed with breast or ovarian cancer. The predicted values from the logistic model can be used to define criteria for identifying Ashkenazi Jewish women with breast cancer who are at high risk of carrying BRCA1 and BRCA2 mutations. The following criteria would identify those at approximately 10% risk: (1) breast cancer <50 years, (2) breast cancer <60 years with a first degree relative with breast cancer <60 years, or (3) breast cancer <70 years and a first or second degree relative with ovarian cancer.

Several reports have suggested that one or both of the trinucleotide repeat polymorphisms in the human androgen receptor (hAR) gene, (CAG)n coding for polyglutamine and (GGC)n coding for polyglycine, may be associated with prostate cancer risk; but no study has investigated their association with disease progression. We present here a study of both hAR trinucleotide repeat polymorphisms not only as they relate to the initial diagnosis but also as they are associated with disease progression after therapy. Lymphocyte DNA samples from 178 British Caucasian prostate cancer patients and 195 control individuals were genotyped by PCR for the (CAG)n and (GGC)n polymorphisms in hAR. Univariate Cox proportional hazard analysis indicated that stage, grade and GGC repeat length were individually significant factors associated with disease-free survival (DFS) and overall survival (OS). The relative risk (RR) of relapse for men with more than 16 GGC repeats was 1.74 (95% CI 1. 08-2.79) and of dying from any cause, 1.98 (1.13-3.45). Adjusting for stage and grade, GGC effects remained but were not significant (RR(DFS)= 1.60, p = 0.052; RR(OS)= 1.65, p = 0.088). The greatest effects were in stage T1-T2 (RR(DFS)= 3.56, 95% CI 1.13-11.21) and grade 1 (RR(DFS)= 6.47, 95% CI 0.57-72.8) tumours. No differences between patient and control allele distributions were found by odds-ratio analysis, nor were trends with stage or grade evident in the proportion of short CAG alleles. Non-significant trends with stage and grade were found in the proportion of short GGC alleles. The (GGC)n polymorphism in this population is a significant predictor of disease outcome. Since the (GGC)(n) effect is strongest in early-stage tumours, this marker may help forecast aggressive behaviour and could be used to identify those patients meriting more radical treatment.

The Li-Fraumeni syndrome (LFS) is a dominant disease whose hallmark is an increased risk of breast cancers, brain tumours, sarcomas, leukaemia and adrenal carcinoma. Some, but not all LFS and Li-Fraumeni-like (LFL) families are caused by TP53 mutations. Bcl10 is a recently identified tumour suppressor reported to be commonly mutated in a wide range of cancers. To investigate the possibility that Bcl10 is a susceptibility gene for LFS and LFL we have analysed 27 LFS/LFL families. No mutations were observed. This indicates that Bcl10 is unlikely to act as a susceptibility gene for LFS and LFL.

The new genetics is having an impact on many areas of healthcare. Diversity in the genetic code accounts for differences in phenotypes between populations and it is becoming apparent that genetic differences may have a role in predisposition to and behaviour of disease. Genetic models suggest that there are two types of genetic predisposition to disease: the so-called high and low penetrance genes. At present, most of the impact on medicine has been from highly penetrant genes, and genetic testing for disease predisposition, particularly for diseases of late onset (e.g. certain cancers) is in its infancy. As a general statement, approximately 5-10% of common cancers are due to such highly penetrant genes. The category of genes that will become of increasing interest is that of the low penetrance genes. Often these are normal variations in genes that result in a slightly increased risk of disease. These are analogous to high blood pressure carrying an increased risk of cardiovascular disease. Once rapid genetic analysis is available for these types of genes, such analysis would be analogous to taking someone's blood pressure in a general practitioner's (GP's) surgery to identify individuals at increased risk of cardiovascular disease. This will produce a revolutionary change in the way we practise medicine. Genetic analysis will become faster and may therefore be more commonplace. It is possible to envisage an era when genetic analysis will become a routine part of primary care to identify changes in low penetrance genes that will confer a 'risk profile' for patients. This will then enable their primary care physicians to advise about primary prevention and even prescribe certain preventive drugs to decrease the risk of certain diseases occurring. This proactive rather than reactive style of practising medicine is potentially exciting, however it carries with it ethical, legal and social implications for how we deal with this new knowledge.

Prostate cancer has been known to run in families for about 40 years and epidemiological studies have demonstrated an increased risk to close relatives of cases. This risk rises markedly when the closeness and number of cases in a cluster increases. There has been considerable debate about the genetic model, in particular whether there is a commoner lower penetrance (moderately increased risk of the disease due to the gene(s)) in addition to contribution from high risk genes. For the first time, molecular results are starting to emerge, indicating the location of high risk genes. These have shown that there is evidence for more than one site of a high risk, gene two sites on chromosome 1 and one on chromosome X. These do not account for all clusters of prostate cancer cases and further genes remain to be discovered. This article also outlines the contribution of the numerous collaborators in the British Prostate Group to the UK Familial Prostate Cancer Study.

We have used single-strand conformation polymorphism (SSCP) analysis to screen for mutations in the BCL10 gene in 81 primary prostate carcinomas, 20 squamous cell cancers of the head and neck, 15 small-cell lung cancer cell lines, 24 renal carcinoma cell lines and 13 sarcoma cell lines. We failed to find evidence of somatically acquired mutations of the BCL10 gene suggesting that BCL10 does not play a major role in the development of these malignancies.

The present study investigated: (1) perception of genetic risk and, (2) the psychological effects of genetic counselling in women with a family history of breast cancer. Using a prospective design, with assessment pre- and post-genetic counselling at clinics and by postal follow-up at 1, 6 and 12 months, attenders at four South London genetic clinics were assessed. Participants included 282 women with a family history of breast cancer. Outcome was measured in terms of mental health, cancer-specific distress and risk perception. High levels of cancer-specific distress were found pre-genetic counselling, with 28% of participants reporting that they worried about breast cancer 'frequently or constantly' and 18% that worry about breast cancer was 'a severe or definite problem'. Following genetic counselling, levels of cancer-specific distress were unchanged. General mental health remained unchanged over time (33% psychiatric cases detected pre-genetic counselling, 27% at 12 months after genetic counselling). Prior to their genetics consultation, participants showed poor knowledge of their lifetime risk of breast cancer since there was no association between their perceived lifetime risk (when they were asked to express this as a 1 in x odds ratio) and their actual risk, when the latter was calculated by the geneticist at the clinic using the CASH model. In contrast, women were more accurate about their risk of breast cancer pre-genetic counselling when this was assessed in broad categorical terms (i.e. very much lower/very much higher than the average woman) with a significant association between this rating and the subsequently calculated CASH risk figure (P = 0.001). Genetic counselling produced a modest shift in the accuracy of perceived lifetime risk, expressed as an odds ratio, which was maintained at 12 months' follow-up. A significant minority failed to benefit from genetic counselling; 77 women continued to over-estimate their risk and maintain high levels of cancer-related worry. Most clinic attenders were inaccurate in their estimates of the population risk of breast cancer with only 24% able to give the correct figure prior to genetic counselling and 36% over-estimating this risk. There was some improvement following genetic counselling with 62% able to give the correct figure, but this information was poorly retained and this figure had dropped to 34% by the 1-year follow-up. The study showed that women attending for genetic counselling are worried about breast cancer, with 34% indicating that they had initiated the referral to the genetic clinic themselves. This anxiety is not alleviated by genetic counselling, although women reported that it was less of a problem at follow-up. Women who continue to over-estimate their risk and worry about breast cancer are likely to go on seeking unnecessary screening if they are not reassured.

Cowden disease (CD) is a rare, autosomal dominant inherited cancer syndrome characterized by multiple benign and malignant lesions in a wide spectrum of tissues. While individuals with CD have an increased risk of breast and thyroid neoplasms, the primary features of CD are hamartomas. The gene for CD has been mapped by linkage analysis to a 6 cM region on the long arm of chromosome 10 at 10q22-23. Loss of heterozygosity (LOH) studies of sporadic follicular thyroid adenomas and carcinomas, both component tumors of CD, have suggested that the putative susceptibility gene for CD is a tumor suppressor gene. Somatic missense and nonsense mutations have recently been identified in breast, prostate, and brain tumor cell lines in a gene encoding a dual specificity phosphatase, PTEN/MMACI, mapped at 10q23.3. Furthermore, germline PTEN/MMACI mutations are associated with CD. In the present study, 20 hamartomas from 11 individuals belonging to ten unrelated families with CD have been examined for LOH of markers flanking and within PTEN/MMACI. Eight of these ten families have germline PTEN/MMACI mutations. LOH involving microsatellite markers within the CD interval, and including PTEN/MMACI, was identified in two fibroadenomas of the breast, a thyroid adenoma, and a pulmonary hamartoma belonging to 3 to 11 (27%) of these patients. The wild-type allele was lost in these hamartomas. Semi-quantitative PCR performed on RNA from hamartomas from three different tissues from a CD patient suggested substantial reduction of PTEN/MMACI RNA levels in all of these tissues. The LOH identified in samples from individuals with CD and the suggestion of allelic loss and reduced transcription in hamartomas from a CD patient provide evidence that PTEN/MMACI functions as a tumor suppressor in CD.

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.

Prostate cancer shows evidence of familial aggregation, particularly at young ages at diagnosis, but the inherited basis of familial prostate cancer is poorly understood. Smith et al. recently found evidence of linkage to markers on 1q, at a locus designated "HPC1," in 91 families with multiple cases of early-onset prostate cancer. Using both parametric and nonparametric methods, we attempted to confirm this finding, in 60 affected related pairs and in 76 families with three or more cases of prostate cancer, but we found no significant evidence of linkage. The estimated proportion of linked families, under a standard autosomal dominant model, was 4%, with an upper 95% confidence limit of 31%. We conclude that the HPC1 locus is responsible for only a minority of familial prostate cancer cases and that it is likely to be most important in families with at least four cases of the disease.

Many epidemiological studies have reported an association between breast and prostate cancer. BRCA2 functions as a tumour-suppressor gene in about 35% of large familial breast-cancer clusters; its role in the pathogenesis of sporadic breast cancer is less clear. We have evaluated immunohistochemical expression of BRCA2 protein and allelic loss of markers at the BRCA2 locus in tissue derived both from sporadic and from familial cases of prostate cancer. Immunohistochemical analysis was performed in 167 paraffin-embedded archival specimens. Normal prostate and 75% (120/160) of prostate-cancer tissue did not express BRCA2 protein. However, 25% (40/160) of cancer cases did express patchy staining; of these, 17% (2711 60) expressed positive nuclear staining in normal glandular tissue adjacent to tumour (either in addition to, or, independent of tumour). Allelic loss is the hallmark of a tumour-suppressor gene. Markers flanking (D13S267, D13S260) and within (D13S171) the BRCA2 gene indicated allelic loss in at least one locus in 23% (17/73) of tumours analyzed. There was no difference in the rates of allelic loss between sporadic and familial tumours, nor was there any association between immunohistochemical staining and allelic loss. Although immunohistochemical staining provided no useful prognostic information, allelic loss at BRCA2 was shown in univariate analysis to be associated with poorer survival (log-rank test, p = 0.046).

Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal dominant disorder with an increased risk for breast and thyroid carcinoma. The diagnosis of CS, as operationally defined by the International Cowden Consortium, is made when a patient, or family, has a combination of pathognomonic major and/or minor criteria. The CS gene has recently been identified as PTEN, which maps at 10q23.3 and encodes a dual specificity phosphatase. PTEN appears to function as a tumour suppressor in CS, with between 13-80% of CS families harbouring germline nonsense, missense, and frameshift mutations predicted to disrupt normal PTEN function. To date, only a small number of tumour suppressor genes, including BRCA1, BRCA2, and p53, have been associated with familial breast or breast/ovarian cancer families. Given the involvement of PTEN in CS, we postulated that PTEN was a likely candidate to play a role in families with a "CS-like" phenotype, but not classical CS. To answer these questions, we gathered a series of patients from families who had features reminiscent of CS but did not meet the Consortium Criteria. Using a combination of denaturing gradient gel electrophoresis (DGGE), temporal temperature gel electrophoresis (TTGE), and sequence analysis, we screened 64 unrelated CS-like subjects for germline mutations in PTEN. A single male with follicular thyroid carcinoma from one of these 64 (2%) CS-like families harboured a germline point mutation, c.209T-->C. This mutation occurred at the last nucleotide of exon 3 and within a region homologous to the cytoskeletal proteins tensin and auxilin. We conclude that germline PTEN mutations play a relatively minor role in CS-like families. In addition, our data would suggest that, for the most part, the strict International Cowden Consortium operational diagnostic criteria for CS are quite robust and should remain in place.

A recent report has provided strong evidence for a major prostate cancer susceptibility locus (HPC1) on chromosome 1q24-25 (Smith et al, 1996). Most inherited cancer susceptibility genes function as tumour-suppressor genes (TSGs). Allelic loss or imbalance in tumour tissue is often the hallmark of a TSG. Studies of allelic loss have not previously implicated the chromosomal region 1q24-25 in prostate cancer. However, analysis of tumour DNA from cases in prostate cancer families has not been reported. In this study, we have evaluated DNA from tissue obtained from small families [3-5 affected members (n = 17)], sibling pairs (n = 15) and sporadic (n = 40) prostate tumours using the three markers from Smith et al (1996) that defined the maximum multipoint linkage lod score. Although widely spaced (12-50 cM), each marker showed evidence of allelic imbalance in only approximately 7.5% of informative tumours. There was no difference between the familial and sporadic cases. We conclude that the incidence of allelic imbalance at HPC1 is low in both sporadic tumours and small prostate cancer families. In this group of patients, HPC1 is unlikely to be acting as a TSG in the development of prostate cancer.

Carcinoma of the male breast is a rare condition. It is even more unusual for a man to present to a breast surgeon regarding an inherited predisposition to developing breast cancer. Nevertheless, this case report illustrates that men with a family history of male or female breast carcinoma may have the same fears of developing a breast cancer as their female counterparts. We believe this to be the first reported case within the UK of a bilateral prophylactic mastectomy for a man.

Background Tamoxifen, a drug with antioestrogenic effects, is predicted to prevent the occurrence of breast cancer, We have undertaken a trial of tamoxifen in healthy women who are at increased risk of breast cancer because of family history. We report a planned interim analysis,Methods Between October, 1986, and April, 1996, we accrued 2494 healthy women aged between 30 and 70 with a family history of breast cancer, They have been randomised (double blind) to receive tamoxifen 20 mg per day orally or placebo for up to 8 years. Follow-up included clinical assessment, annual mammography, and assessment of toxicity and compliance. The primary endpoint was the occurrence of breast cancer, which was analysed on an intention-to-treat basis with a survival curve.Findings With a median follow-up of 70 months, 2471 women (tamoxifen 1238, placebo 1233) were suitable for analysis, The groups were evenly matched at baseline, and compliance was good. The overall frequency of breast cancer is the same for women on tamoxifen or placebo (tamoxifen 34, placebo 36, relative risk 1.06 [95% CI 0.7-1.7], p=0.8). Participants who were already on hormone-replacement therapy when they entered the study had an increased risk of breast cancer compared with nonusers. Those participants who started such therapy while on trial had a significantly reduced risk. The safety profile of tamoxifen was as expected.Interpretation We have been unable to show any effect of tamoxifen on breast-cancer incidence in healthy women, contrary to the report from the NSABP-P1 study showing a 45% reduction in healthy women given tamoxifen versus placebo. Differences in the study populations for the two trials may underlie these conflicting findings: eligibility in our trial was based predominantly on a strong family history of breast cancer whereas in the NSABP trial was mostly based on non-genetic risk factors. The importance of oestrogen promotion may vary between such populations.

The current study has two aims: (1) to look at people's recall of risk information after genetic counselling and (2) to determine the impact of receiving an audiotape of the genetic consultation on level of recall, cancer related worry, and women's uptake of risk management methods. Using a prospective randomised controlled design, subjects receiving an audiotape were compared with a standard consultation group. Participants were drawn from attenders at the genetic clinics of two London hospitals and included 115 women with a family history of breast cancer. Assessment of perceived genetic risk, mental health, cancer worry, and health behaviour was made before counselling at the clinic (baseline) and by postal follow up. Usefulness of audiotapes and satisfaction with the clinical service was assessed by study specific measures. The data indicate that cancer worry is reduced by provision of an audiotape of the genetic consultation. Recall of the genetic risk figure, however, is not affected by provision of an audiotape and neither is it related to women's overall perception of being more or less at risk of breast cancer than the average woman. Forty-one percent of women accurately recalled their personal risk of breast cancer at one month follow up; however, 25% overestimated, 11% underestimated, and 23% could not remember or did not know their breast cancer risk. Recall of the risk figure is more accurate when the clinical geneticist has given this to the woman as an odds ratio rather than in other formats. Subsequent health behaviour is unaffected by whether women have an audiotape record of their genetic consultation. Results suggest that having a precise risk figure may be less important than women taking away from the consultation an impression that something can be offered to help them manage that risk. Provision of an audiotape of the consultation is of limited usefulness. The need for psychological care to be better integrated into genetic counselling at cancer family clinics was highlighted by the study. The results are discussed in terms of future service development.

There is evidence that predisposition to cancer has a genetic component. Genetic models have suggested that there is at least one highly penetrant gene predisposing to this disease. The oncogene MXI1 on chromosome band 10q24-25 is mutated in a proportion of prostate tumours and loss of heterozygosity occurs at this site, suggesting the location of a tumour suppressor in this region. To investigate the possibility that MXI1 may be involved in inherited susceptibility to prostate cancer, we have sequenced the HLH and ZIP regions of the gene in 38 families with either three cases of prostate cancer or two affected siblings both diagnosed below the age of 67 years. These are the areas within which mutations have been described in some sporadic prostate cancers. No mutations were found in these two important coding regions and we therefore conclude that MXI1 does not make a major contribution to prostate cancer susceptibility.

In the present study, leukocyte DNA from 143 patients with familial clustering of breast and/or ovarian cancer and tumour DNA from 96 breast carcinomas were screened for base mutations in the estrogen receptor gene (ESR), Three patients with a family history of cancer were carrying a GLy160Cys germ line substitution. This alteration was also detected in eight (four females and four males) of 729 con trols (366 female, 363 males), indicating that the substitution probably represents a polymorphism. However, in the 229 female controls in whom family history of cancer was known, one of two who had a sister with breast cancer was carrying the variant allele. Hence, a possible clinical significance of the glycine into cysteine cannot be completely ruled out and should be further investigated. Somatic mutations were not detected in any of the tumours studied, and the present data do not provide support for somatic ESR base mutations as an important mechanism for hormonal therapy resistance in estrogen receptor-positive breast carcinomas. (C) 1997 Wiley-Liss Inc.

Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23.

The present study set out to evaluate perceptions of risk, psychological morbidity and health behaviours in women with a family history of breast cancer who have attended genetic counselling and determine how these differ from general population risk women. Data were collected from 62 genetic counselees (cases) attending the Royal Marsden and Mayday University Hospital genetic counselling services and 62 matched GP attenders (controls). Levels of general psychological morbidity were found to be similar between cases and controls; however, cases reported significantly higher breast cancer-specific distress despite clinic attendance [mean (s.d.) total Impact of Event Scale score, 14.1 (14.3) cases; 2.4 (6.7) controls, P < 0.001]. Although cases perceived themselves to be more susceptible to breast cancer, many women failed correctly to recall risk figures provided by the clinic; 66% could not accurately recall their own lifetime chance. Clinics appeared to have a positive impact on preventive behaviours and cases tended to engage more regularly in breast self-examination (monthly, 66% of cases vs 47% of controls), although few differences were found between groups in terms of health beliefs. We conclude that counselees and GP controls showed considerable similarities on many of the outcome measures, and risk of breast cancer was not predictive of greater psychological morbidity; although cases were more vulnerable to cancer-specific distress. Despite genetic counselling, many cases continued to perceive their risk of breast cancer inaccurately.

The identification of the BRCA1 gene may prove a mixed blessing in the short term. First, the demand for testing might outstrip available resources, the ethics of testing are complex and the advice to give someone who tests positive is as yet unclear. Furthermore, the psychological dynamics within such families have not yet been considered seriously. As these families might be widespread, there will inevitably be problems involving clinical genetic centres in different parts of the country, or for that matter, in different areas of the world. In this paper we provide a case report, which might be considered an adumbration of things to come. The proband in this story (a co-author) was known to have inherited a genetic predisposition to cancer. This was because her identical twin had already developed the disease and she came from a kindred with a very high probability for carrying a dominant breast cancer gene in the germ line. We describe the personal reactions of an individual woman faced with these difficult decisions, the impact on her family and the impact on the clinical genetic services in different parts of the country. Our experience could help to provide a template for the development of regional services once genetic testing for predisposition to breast cancer becomes widely available.

Data are reported on an investigation of the impact of genetic testing in two families with a > 95% probability of linkage to the BRCA1 Breast/Ovarian cancer predispostion gene. Levels of psychological morbidity and cancer specific concerns in this highly selected group were not unusually high. At least half of the sample had no specific prior expectation regarding their gene carrier status. However, there was an indication that an unanticipated unfavourable genetic test result can cause subsequent psychological distress. Uptake of testing in this research sample was 41% overall and was higher (59%) in females. This is likely to have important resource implications if this level of uptake is found when genetic testing is extended outside such research cohorts.

Since the majority of germline mutations in the TP53 gene seem to occur in LFS or LFL families, and these are rare, research is best conducted in a collaborative setting (Li and Fraumeni, in press). In a report from a meeting at Bethesda in 1993, the following areas were outlined for collaborative study: the correlation (if any) of phenotypes with specific mutation; age specific penetrance; cumulative cancer incidence; gender differences in tumour development in carriers; the effects of DNA damaging agents on individuals with a TP53 mutation; the frequency of TP53 germline mutations in cohorts of patients with rare childhood tumours (eg adrenocortical carcinoma); and the psychosocial aspects of predictive TP53 testing. In addition, if, as seems likely from recent data, X irradiation in these individuals induces DNA damage that is tolerated, urgent collaborative studies are needed to investigate new methods of screening, such as magnetic resonance imaging. Treatment modalities should be carefully chosen, and for this reason alone, predictive testing may be desirable in all LFS and LFL families. Individuals carrying TP53 mutations could be offered chemoprevention within trials in an effort to reduce their mortality from cancer.

IN Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2, was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2. Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.

The 9p21 region of human chromosome 3 is a hot spot for chromosomal aberrations in both cultured cell lines and primary tumors. This region contains a gene, P16 (also called MTS1, CDKN2 and p16(INK4)) that encodes a presumptive negative cell cycle regulator called p16. P1G is deleted or mutated at high frequency is a variety of tumor cell lines including melanoma and bladder carcinoma lines. As such, if is likely to be a tumor suppresser gene. Here we show that P1G is mutated in primary bladder carcinomas (3 of 33) and melanomas (5 of 34). These findings support studies that show, P16 mutations are not solely a product of growth, in tissue culture but rather are involved in formation of tumors in vivo Some bladder primary tumors and some bladder and melanoma tumor cell lines contain mutations is both P16 and P53 at frequencies that suggest that p53 and p16 function in different pathways, each of which is important in suppressing malignant transformation.

A small proportion of breast cancer (perhaps about 5%) and a higher proportion of early onset cases are due to the inheritance of mutations in dominant susceptibility genes which confer a high lifetime risk of the disease. This would equate to about 1250 cases per year in the U.K. and 9000 in the U.S.A. Even within these cases, there is genetic heterogeneity, i.e. there are several genes involved, each giving rise to different patterns of other cancers associated with the familial breast cancer. One such gene (p53) has been identified and a second (BRCA1) has been precisely mapped in the human genome, but further breast cancer predisposition genes remain to be identified. In addition, there are other genes which confer a lower risk of the disease, but may account for a larger proportion of cases, the most important example to date being ataxia telangiectasia. The identification of these genes will enable the entity of familial breast cancer to be more precisely defined and has implications for management of gene carriers with breast cancer and their relatives who are at risk. A major consideration in this new area of cancer genetics is that the identification of gene carriers may become possible on a large scale and this raises ethical and social issues.

Cowden syndrome is an autosomal dominant condition of multiple hamartomas. Patients with this phakomatosis have an increased risk of breast cancer and thyroid tumours. Lhermitte-Duclos disease is usually a sporadic condition of cerebellar ganglion cell hypertrophy, ataxia, mental retardation, and self-limited seizure disorder. We describe a three generation family with Cowden syndrome and Lhermitte-Duclos disease. Karyotyping performed on the peripheral lymphocytes of the proband and her affected mother showed a 46,XX complement. Single strand conformational polymorphism analysis failed to show any germline p53 mutations as a cause of the syndrome in this family.

A locus for familial melanoma, MLM, has been mapped within the same interval on chromosome 9p21 as the gene for a putative cell cycle regulator, p16(INK4)(CDKN2) MTS1. This gene is homozygously deleted from many tumour cell lines including melanomas, suggesting that CDKN2 is a good candidate for MLM. We have analysed CDKN2 coding sequences in pedigrees segregating 9p melanoma susceptibility and 38 other melanoma-prone families. in only two families were potential predisposing mutations identified. No evidence was found for heterozygous deletions of CDKN2 in the germline of melanoma-prone individuals. The low frequency of potential predisposing mutations detected suggests that either the majority of mutations fall outside the CDKN2 coding sequence or that CDKN2 is not MLM.

The TP53 protein is proving to be central to cell cycle control after exposure to DNA damage, and every week a new feature of its role in the regulation of cell division is described. TP53 is the most commonly altered oncogene in human tumours and is involved in the development of both sporadic and some hereditary breast tumours. Although there is no doubt that germline mutations in the TP53 gene carry a high risk of early onset breast cancer, and the gene is mutated somatically in a proportion of preinvasive and invasive breast cancers, it is not usually the initiating genetic event in most breast tumours. It does, however, seem to be an independent prognostic factor for survival and could prove useful in clinical management of node negative breast cancer patients. There has been an explosion of reports about the function of the TP53 protein--in particular, it seems to have a central role in the monitoring of some types of DNA damage. This role may prove to be the most important aspect of its association with breast cancer development, both as a prognostic factor and as a handle for treatment.

One hundred and thirty patients with soft tissue sarcoma of the head and neck were treated at the Royal Marsden Hospital between 1944 and 1988. Pathological review was possible in 103 of these cases; only pathologically reviewed cases have been analysed. The median age at presentation was 36 years, and 53% were male. Four had neurofibromatosis type I, and one previous bilateral retinoblastoma. Six had undergone previous radiotherapy, 12 to 45 years prior to developing sarcoma. The tumours were < or = 5 cm in 78% of cases and high grade in 48%. Only one patient presented with lymph node metastases and only one with distant metastases (to lung). Malignant fibrous histiocytoma was the commonest histological type, occurring in 30 cases. The overall 5 year survival was 50% (95% CI 39-60). Local tumour was the cause of death in 63% of cases and 5 year local control was only 47% (95% CI 36-58) with local recurrence occurring as late as 15 years after treatment. The only favourable independent prognostic factor for survival was the ability to perform surgery (other than biopsy), with or without radiotherapy, as opposed to radiotherapy alone (hazard ratio 0.39; P = 0.003). Only one patient had a biopsy with no further treatment. Favourable independent prognostic factors for local control at 5 years were site (tumours of the head as opposed to the neck, hazard ratio 0.42; P = 0.02) and modality of treatment (combined surgery and radiotherapy compared to either alone, hazard ratio 0.31; P = 0.002). Patients in the combined modality and single treatment modality groups were well balanced for T stage, grade and tumour site. The patients in the combined treatment group had less extensive surgery, yet their local recurrence-free survival was longer. Unlike soft tissue sarcomas at other sites, those in the head and neck region more often cause death by local recurrence. The addition of radiotherapy to surgery may result in longer local recurrence-free survival.

Paraffin sections from 32 patients with primary medulloblastoma were analysed by flow cytometry for DNA ploidy and proliferative index to assess the value of these measurements in determining prognosis. Twenty-seven samples were informative. Of these 27 patients, 8 had had a total resection. The tumors were diploid in 13 patients and aneuploid in 14. Neither ploidy nor S-phase fraction were prognostic factors for survival, even when considered in conjunction with the type of surgery performed. This is in contrast to other published data, emphasising the need for large multicentre studies of biological prognostic factors in this rare tumour.

We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C-->T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations.

Recent studies have demonstrated that families with the Li-Fraumeni syndrome carry inherited point mutations of the p53 gene. In the present study 25 families with strong histories of breast cancer were screened for the presence of such mutations. Polymerase chain reaction products of exons 5-9 of the p53 gene were examined by single-stranded conformational polymorphism analysis and, in addition, exon 7 was further screened by direct sequencing. No mutations were detected in constitutive DNA by either method. These results indicate that familial breast cancer does not usually result from germline point mutations in the p53 gene.

Sarcoid-type pulmonary lymphadenopathy associated with testicular cancer is a rare condition which has been previously reported in only 14 cases. Earlier case reports have failed to distinguish between generalized sarcoidosis as opposed to a local granulomatous reaction to tumour. We describe a further 8 cases of the association and provide strong supportive evidence for systemic sarcoidosis in 5 of our patients. In 3 of our patients with systemic sarcoidosis there was coexisting testicular cancer requiring additional treatment. We therefore advise caution in the interpretation of the clinical and histological findings in these patients, and recommend thorough investigation of all such cases.

Forty-four patients with Hodgkin's disease (HD) which relapsed after chemotherapy were treated with salvage radiotherapy (S-RT) with curative intent. Patients were aged 7 to 80 years (median 32 years) at the time of S-RT and the median follow-up from S-RT was 5 years (1-15). Nine patients had recurrent HD following first-line chemotherapy and thirty five patients had refractory HD. Salvage therapy consisted of radiotherapy alone in 25 and combined chemotherapy and radiotherapy in 19 patients. The overall CR rate of salvage therapy was 66%. The overall median survival of 44 patients was 4.6 years from S-RT with 46% 5 year and 40% 10 year survivals. Age (greater than 40 years) and progression free interval (less than or equal to 1 year) were adverse independent prognostic factors for survival on multivariate analysis. The 5 and 10 year progression free survivals were 38% and 23% respectively. Adverse independent prognostic factors for progression-free survival were extranodal site of recurrence and short progression free interval (less than or equal to 1 year). We conclude that radiotherapy with or without chemotherapy has a role in the salvage of patients failing chemotherapy, particularly in those with nodal disease and progression-free interval greater than 1 year.

Between 1971 and 1988, 20 patients with previously undiagnosed non-Hodgkin's lymphoma (NHL), of intermediate or high grade histology presented with extradural spinal cord compression. All had decompressive surgery. The first treatment after surgery was chemotherapy in nine and radiotherapy in 11 patients. At presentation 15% were ambulant and this improved to 55% after surgery; urinary continence improved from 30 to 80%. Mobility and sphincter control remained unchanged, regardless of subsequent therapy. Chemotherapy as the initial treatment modality after surgery, either alone or in combination with radiotherapy, did not jeopardise functional outcome. Mobility after surgery was an independent prognostic factor for survival, when corrected for age and stage at presentation (P = 0.04). The treatment of intermediate and high grade NHL presenting with spinal cord compression should be based on histology, extent of disease and age, as with other sites of presentation, but should also take into consideration the prognostic importance of post-surgical mobility.

To evaluate whether hormone replacement therapy affects survival in women who have undergone bilateral salphingo-oophorectomy because of epithelial ovarian cancer.

Quality of life and limb function were studied in 54 patients who were disease-free 2 or more years after limb-conserving treatment for soft tissue sarcoma of the leg or pelvic girdle. Tumours of the thigh predominated (25 patients) and the mean tumour size was 9.9 cm. 41 patients had been treated with a combination of surgery and radiotherapy (29 with conventional and 12 with high dose), 12 with surgery alone and one with irradiation and intra-arterial doxorubicin. Only 15 patients had a normal range of movement in all lower limb joints and only 12 had normal power in all muscle groups; tumours of the lower leg were particularly unfavourable in this respect. Gait was normal in 42 patients but 8 required a walking aid and 4 a joint support. 16 had detectable lymphoedema but only 2 needed to wear compression hosiery. 35 patients still experienced pain at some time but only 6 required analgesia. However, when assessed by questionnaire for locomotion, grooming and home/leisure/vocational activities, 37 patients (68%) reported excellent function, and only 2 had moderate impairment. Function loss was most marked in leisure (25 patients) and vocational (8) activities, but was mild in 66% of cases. Multivariate analysis was carried out to determine the prognostic factors for poor limb function. The results suggested that overall functional score was predominantly determined by gait (P less than 0.001), muscle power or range of movement (P less than 0.001), with increasing age, female sex and the use of radiotherapy poor prognostic factors. Reduced muscle power or range of movement were the major factors determining gait (P less than 0.02) with the use of radiotherapy the significant prognostic factor for both in the conventionally treated group. Doses in excess of 60 Gy resulted in increased fibrosis and a worse functional outcome. Extent of surgery was not an independent prognostic factor for limb function, although univariate analysis suggested an association with range of movement in the conventionally treated group (P less than 0.025). Despite significant objective loss of range of movement and muscle power patients retain excellent limb function and quality of life following limb conserving treatment. For optimal function, radiotherapy should be given with small fractions to a dose not exceeding 60 Gy.

This paper presents 10 patients with a diagnosis of testicular tumour in whom computed tomography (CT) at staging or follow-up demonstrated abnormalities which mimic the appearance of metastatic testicular tumour. The entities mimicking metastases were sarcoidosis, mushroom worker's lung, lymphoma and phaeochromocytoma. Representative examples of these lesions are illustrated and features which may enable the radiologist to differentiate them from metastatic testicular tumour are discussed.

The pharmacokinetics of carboplatin and etoposide were studied in four testicular teratoma patients receiving four courses each of combination chemotherapy consisting of etoposide (120 mg/m2 daily x 3); bleomycin (30 mg weekly) and carboplatin. The carboplatin dose was calculated so as to achieve a constant area under the plasma concentration vs time curve (AUC) of 4.5 mg carboplatin/ml x min by using the formula: dose = 4.5 x (GFR + 25), where GFR is the absolute glomerular filtration rate measured by 51Cr-EDTA clearance. Carboplatin was given on either day 1 or day 2 of each course and pharmacokinetic studies were carried out in each patient on two courses. Etoposide pharmacokinetics were also studied on two separate courses in each patient on the day on which carboplatin was given and on a day when etoposide was given alone. The pharmacokinetics of carboplatin were the same on both the first and second courses, on which studies were carried out with overall mean +/- SD values (n = 8) of 4.8 +/- 0.6 mg/ml x min, 94 +/- 21 min, 129 +/- 21 min, 20.1 +/- 5.41, 155 +/- 33 ml/min and 102 +/- 24 ml/min for the AUC, beta-phase half-life (t 1/2 beta), mean residence time (MRT), volume of distribution (Vd) and total body (TCLR) and renal clearances (RCLR), respectively. The renal clearance of carboplatin was not significantly different from the GFR (132 +/- 32 ml/min). Etoposide pharmacokinetics were also the same on the two courses studied, with overall mean values +/- SD (n = 8) of: AUC = 5.1 +/- 0.9 mg/ml x min, t 1/2 alpha = 40 +/- 9 min, t 1/2 beta = 257 +/- 21 min, MRT = 292 +/- 25 min, Vd = 13.3 +/- 1.31, TCLR = 46 +/- 9 ml/min and RCLR = 17.6 +/- 6.3 ml/min when the drug was given alone and AUC = 5.3 +/- 0.6 mg/ml x min, t 1/2 alpha = 34 +/- 6 min, t 1/2 beta = 242 +/- 25 min, MRT = 292 +/- 25 min, Vd = 12.5 +/- 1.81, TCLR = 43 +/- 6 ml/min and RCLR = 13.4 +/- 3.5 ml/min when it was given in combination with carboplatin. Thus, the equation used to determine the carboplatin accurately predicted the AUC observed and the pharmacokinetics of etoposide were not altered by concurrent carboplatin administration. The therapeutic efficacy and toxicity of the carboplatin-etoposide-bleomycin combination will be compared to those of cisplatin, etoposide and bleomycin in a randomised trial.