Publications

BACKGROUND: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). METHODS: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). RESULTS: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors. CONCLUSIONS: This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783-. ©2012 AACR.

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6×10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8×10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2×10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8×10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8×10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3×10(-7), p(heterogeneity) = 5.1×10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795-803. ©2012 AACR.

We conducted a genome-wide association study of male breast cancer using 823 cases and 2,795 controls of European ancestry with validation in independent sample sets totalling 438 cases and 474 controls. A novel variant in RAD51B (14q24.1) was significantly associated with male breast cancer risk (P = 3.02 x 10-13, odds ratio (OR) = 1.57). TOX3 (16q12.1) was also a susceptibility locus (P = 3.87 x 10-15, OR = 1.50).

Tamoxifen is an effective treatment for breast cancer but an undesirable side-effect is an increased risk of endometrial cancer, particularly rare tumor types associated with poor prognosis. We investigated whether tamoxifen therapy increases mortality among breast cancer patients subsequently diagnosed with endometrial cancer.

To investigate breast cancer risk after supradiaphragmatic radiotherapy administered to young women with Hodgkin's lymphoma (HL) in a much larger cohort than previously to provide data for patient follow-up and screening individualized according to treatment type, age, and time point during follow-up.

The authors examined the effect of women's lifestyles on the timing of natural menopause using data from a cross-sectional questionnaire used in the United Kingdom-based Breakthrough Generations Study in 2003-2011. The analyses included 50,678 women (21,511 who had experienced a natural menopause) who were 40-98 years of age at study entry and did not have a history of breast cancer. Cox competing risks proportional hazards models were fitted to examine the relation of age at natural menopause to lifestyle and anthropometric factors. Results were adjusted for age at reporting, smoking status at menopause, parity, and body mass index at age 40 years, as appropriate. All P values were 2-sided. High adult weight (P(trend) < 0.001), high body mass index (P(trend) < 0.001), weight gain between the ages of 20 and 40 years (P(trend) = 0.01), not smoking (P < 0.001), increased alcohol consumption (P(trend) < 0.001), regular strenuous exercise (P < 0.01), and not being a vegetarian (P < 0.001) were associated with older age at menopause. Neither height nor history of an eating disorder was associated with menopausal age. These findings show the importance of lifestyle factors in determining menopausal age.

Few studies have evaluated the association between DNA methylation in white blood cells (WBC) and the risk of breast cancer. The evaluation of WBC DNA methylation as a biomarker of cancer risk is of particular importance as peripheral blood is often available in prospective cohorts and easier to obtain than tumor or normal tissues. Here, we used prediagnostic blood samples from three studies to analyze WBC DNA methylation of two ATM intragenic loci (ATMmvp2a and ATMmvp2b) and genome-wide DNA methylation in long interspersed nuclear element-1 (LINE1) repetitive elements. Samples were from a case-control study derived from a cohort of high-risk breast cancer families (KConFab) and nested case-control studies in two prospective cohorts: Breakthrough Generations Study (BGS) and European Prospective Investigation into Cancer and Nutrition (EPIC). Bisulfite pyrosequencing was used to quantify methylation from 640 incident cases of invasive breast cancer and 741 controls. Quintile analyses for ATMmvp2a showed an increased risk of breast cancer limited to women in the highest quintile [OR, 1.89; 95% confidence interval (CI), 1.36-2.64; P = 1.64 × 10(-4)]. We found no significant differences in estimates across studies or in analyses stratified by family history or menopausal status. However, a more consistent association was observed in younger than in older women and individually significant in KConFab and BGS, but not EPIC. We observed no differences in LINE1 or ATMmvp2b methylation between cases and controls. Together, our findings indicate that WBC DNA methylation levels at ATM could be a marker of breast cancer risk and further support the pursuit of epigenome-wide association studies of peripheral blood DNA methylation.

BackgroundEpidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women.MethodsWe measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided.Resultsrs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82).ConclusionsGenetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

Women treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rs1219648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P = .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk.

Over recent years mobile phone use has become near ubiquitous, and there has been public interest in their possible health effects. RF exposures also occur from several other sources. Epidemiological evidence on potential health effects of radiofrequency fields (RF) in man has come from studies of people exposed to RF through work and hobbies or through residence near RF transmitters, and studies of people using mobile phones. The latter have particularly focused on cancer risks, using both case-control and cohort methodology. There are limitations in the data available, however, including poor or potentially biased exposure assessment in many studies, and for mobile phones restriction in the exposure periods studied because mobile phones have only become widely used relatively recently.

OBJECTIVES: To assess familial resemblance for height, arm span, and components of these, and differences between concordance for short and tall heights. METHODS: We examined whether female relatives were similar for six anthropometric measurements (height, arm span, leg, trunk and arm length, and leg:trunk length ratio). Subjects were 31,622 related individuals aged 16-102 yr participating in the UK Breakthrough Generations Study. Height and arm span were self-reported, limb and trunk length were measured in a subset (N = 508) by study investigators, and paternal height was reported by the daughter. Data were analyzed using correlations and Poisson regression. RESULTS: Correlation coefficients within families were 0.4 for height, 0.3 for arm span, and 0.5 for leg length, trunk length, leg:trunk ratio, and arm length. Women had a relative risk (RR) of being short (i.e., in the lowest height quintile) of 2.3 (95% confidence interval [CI] = 2.1-2.5) if their mother was short, 2.1 (95% CI = 1.9-2.3) if their father was short, and 3.7 (95% CI = 3.4-4.0) if both parents were short. RRs of being tall (i.e., in the highest height quintile) were 2.3 (95% CI = 2.1-2.5), 2.4 (95% CI = 2.2-2.6), and 4.4 (95% CI = 4.1-4.8) if their mother, father or both were tall, respectively. CONCLUSIONS: We have shown, for the first time, that leg:trunk length ratio and arm length aggregate within families. Concordance seemed to be stronger for tall than short heights. Am. J. Hum. Biol., 2011. © 2011 Wiley Periodicals, Inc.

We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkin's lymphoma (HL) in a much larger cohort than any yet published, to our knowledge.

A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.

Background: The rapid increase in mobile telephone use has generated concern about possible health risks of radiofrequency electromagnetic fields from these devices. Methods: A case-control study of 1105 patients with newly diagnosed acoustic neuroma (vestibular schwannoma) and 2145 controls was conducted in 13 countries using a common protocol. Past mobile phone use was assessed by personal interview. In the primary analysis, exposure time was censored at one year before the reference date (date of diagnosis for cases and date of diagnosis of the matched case for controls); analyses censoring exposure at five years before the reference date were also done to allow for a possible longer latent period. Results: The odds ratio (OR) of acoustic neuroma with ever having been a regular mobile phone user was 0.85 (95% confidence interval 0.69-1.04). The OR for >= 10 years after first regular mobile phone use was 0.76 (0.52-1.11). There was no trend of increasing ORs with increasing cumulative call time or cumulative number of calls, with the lowest OR (0.48 (0.30-0.78)) observed in the 9th decile of cumulative call time. In the 10th decile (>= 1640 h) of cumulative call time, the OR was 1.32 (0.88-1.97); there were, however, implausible values of reported use in those with >= 1640 h of accumulated mobile phone use. With censoring at 5 years before the reference date the OR for >= 10 years after first regular mobile phone use was 0.83 (0.58-1.19) and for >= 1640 h of cumulative call time it was 2.79(1.51-5.16). but again with no trend in the lower nine deciles and with the lowest OR in the 9th decile. In general, ORs were not greater in subjects who reported usual phone use on the same side of the head as their tumour than in those who reported it on the opposite side, but it was greater in those in the 10th decile of cumulative hours of use. Conclusions: There was no increase in risk of acoustic neuroma with ever regular use of a mobile phone or for users who began regular use 10 years or more before the reference date. Elevated odds ratios observed at the highest level of cumulative call time could be due to chance, reporting bias or a causal effect. As acoustic neuroma is usually a slowly growing tumour, the interval between introduction of mobile phones and occurrence of the tumour might have been too short to observe an effect, if there is one. (C) 2011 Elsevier Ltd. All rights reserved.

Background: In the past 15 years, mobile telephone use has evolved from an uncommon activity to one with > 4.6 billion subscriptions worldwide. However, there is public concern about the possibility that mobile phones might cause cancer, especially brain tumors. Objectives: We reviewed the evidence on whether mobile phone use raises the risk of the main types of brain tumor—glioma and meningioma—with a particular focus on the recent publication of the largest epidemiologic study yet: the 13-country Interphone Study. Discussion: Methodological deficits limit the conclusions that can be drawn from the Interphone study, but its results, along with those from other epidemiologic, biological, and animal studies and brain tumor incidence trends, suggest that within about 10–15 years after first use of mobile phones there is unlikely to be a material increase in the risk of brain tumors in adults. Data for childhood tumors and for periods beyond 15 years are currently lacking. Conclusions: Although there remains some uncertainty, the trend in the accumulating evidence is increasingly against the hypothesis that mobile phone use can cause brain tumors in adults.

Male breast cancer accounts for approximately 1% of all breast cancer. To date, risk factors for male breast cancer are poorly defined, but certain risk factors and genetic features appear common to both male and female breast cancer. Genome-wide association studies (GWAS) have recently identified common single nucleotide polymorphisms (SNPs) that influence female breast cancer risk; 12 of these have been independently replicated. To examine if these variants contribute to male breast cancer risk, we genotyped 433 male breast cancer cases and 1,569 controls. Five SNPs showed a statistically significant association with male breast cancer: rs13387042 (2q35) (odds ratio (OR)  = 1.30, p = 7.98×10⁻⁴), rs10941679 (5p12) (OR = 1.26, p = 0.007), rs9383938 (6q25.1) (OR = 1.39, p = 0.004), rs2981579 (FGFR2) (OR = 1.18, p = 0.03), and rs3803662 (TOX3) (OR = 1.48, p = 4.04×10⁻⁶). Comparing the ORs for male breast cancer with the published ORs for female breast cancer, three SNPs--rs13387042 (2q35), rs3803662 (TOX3), and rs6504950 (COX11)--showed significant differences in ORs (p<0.05) between sexes. Breast cancer is a heterogeneous disease; the relative risks associated with loci identified to date show subtype and, based on these data, gender specificity. Additional studies of well-defined patient subgroups could provide further insight into the biological basis of breast cancer development.

A model has been proposed whereby melanomas arise through two distinct pathways dependent on the relative influence of host susceptibility and sun exposure. Such pathways may explain site-specific patterns of melanoma occurrence. To explore this model, we investigated the relationship between melanoma risk and general markers of acute (recalled sunburns) and chronic (prevalent solar keratoses) sun exposure, stratified by anatomic site and host phenotype. Our working hypothesis was that head and neck melanomas have stronger associations with solar keratoses and weaker associations with sunburn than trunk melanomas. We conducted a collaborative analysis using original data from women subjects of 11 case-control studies of melanoma (2,575 cases, 3,241 controls). We adjusted for potential confounding effects of sunlamp use and sunbathing. The magnitude of sunburn associations did not differ significantly by melanoma site, nevus count or histologic subtype of melanoma. Across all sites, relative risk of melanoma increased with an increasing number of reported lifetime "painful" sunburns, lifetime "severe" sunburns and "severe" sunburns in youth (p(trend) < 0.001), with pooled odds ratios (pORs) for the highest category of sunburns versus no sunburns of 3.22 [95% confidence interval (CI) 2.04-5.09] for lifetime "painful" sunburns, 2.10 (95%CI 1.30-3.38) for lifetime "severe" sunburns and 2.43 (95%CI 1.61-3.65) for "severe" sunburns in youth. Solar keratoses strongly increased the risk of head and neck melanoma (pOR 4.91, 95%CI 2.10-11.46), but data were insufficient to assess risk for other sites. Reported sunburn is strongly associated with melanoma on all major body sites.

Women become infertile approximately 10 years before menopause, and as more women delay childbirth into their 30s, the number of women who experience infertility is likely to increase. Tests that predict the timing of menopause would allow women to make informed reproductive decisions. Current predictors are only effective just prior to menopause, and there are no long-range indicators. Age at menopause and early menopause (EM) are highly heritable, suggesting a genetic aetiology. Recent genome-wide scans have identified four loci associated with variation in the age of normal menopause (40-60 years). We aimed to determine whether theses loci are also risk factors for EM. We tested the four menopause-associated genetic variants in a cohort of approximately 2000 women with menopause≤45 years from the Breakthrough Generations Study (BGS). All four variants significantly increased the odds of having EM. Comparing the 4.5% of individuals with the lowest number of risk alleles (two or three) with the 3.0% with the highest number (eight risk alleles), the odds ratio was 4.1 (95% CI 2.4-7.1, P=4.0×10(-7)). In combination, the four variants discriminated EM cases with a receiver operator characteristic area under the curve of 0.6. Four common genetic variants identified by genome-wide association studies, had a significant impact on the odds of having EM in an independent cohort from the BGS. The discriminative power is still limited, but as more variants are discovered they may be useful for predicting reproductive lifespan.

Morris DH, Jones ME, Schoemaker MJ, Ashworth A, Swerdlow AJ. Familial concordance for age at menarche: analyses from the Breakthrough Generations Study. Paediatric and Perinatal Epidemiology 2011; 25: 306-311. Age at menarche is correlated within families, but estimates of the heritability of menarcheal age have a wide range (0.45-0.95). We examined the familial resemblance for age at menarche and the extent to which this is due to genetic and shared environmental factors. Between 2003 and 2010 data were retrospectively collected by questionnaire from participants within the UK-based Breakthrough Generations Study. These analyses included 25 970 female participants aged 16-98 with at least one female relative who was also a study participant. A woman's menarche was significantly delayed for each yearly increase in the menarcheal age of her monozygotic twin (average increase = 7.2 months, P < 0.001), dizygotic twin (average increase = 3.0 months, P = 0.03), older sister (average increase = 3.3 months, P < 0.001), mother (average increase = 3.4 months, P < 0.001), maternal grandmother (average increase = 1.5 months, P = 0.04), maternal aunt (average increase = 1.4 months, P < 0.001) and paternal aunt (average increase = 3.0 months, P < 0.001). There was not a significant association between the menarcheal ages of half-sister pairs or of paternal grandmother-granddaughter pairs, based on small numbers. Heritability was estimated as 0.57 [95% confidence interval 0.53, 0.61]. Shared environmental factors did not have an effect in the model. In conclusion, approximately half of the variation in age at menarche was attributable to additive genetic effects with the remainder attributable to non-shared environmental effects.

OBJECTIVE:: Existing estimates of the heritability of menopause age have a wide range. Furthermore, few studies have analyzed to what extent familial similarities might reflect shared environment, rather than shared genes. We therefore analyzed familial concordance for age at natural menopause and the effects of shared genetic and environmental factors on this concordance. METHODS:: Participants were 2,060 individuals comprising first-degree relatives, aged 31 to 90 years, and participating in the UK Breakthrough Generations Study. Menopause data were collected using a self-administered questionnaire and analyzed using logistic regression and variance-components models. RESULTS:: Women were at an increased risk of early menopause (≤45 y) if their mother (odds ratio, 6.2; P < 0.001) or nontwin sister (odds ratio, 5.5; P < 0.001) had had an early menopause. Likewise, women had an increased risk of late menopause (≥54 y) if their relative had had a late menopause (mother: odds ratio, 6.1; P < 0.01; nontwin sister: odds ratio, 2.3; P < 0.001). Estimated heritability was 41.6% (P < 0.01), with an additional 13.6% (P = 0.02) of the variation in menopause age attributed to environmental factors shared by sisters. CONCLUSIONS:: We confirm that early menopause aggregates within families and show, for the first time, that there is also strong familial concordance for late menopause. Both genes and shared environment were the source of variation in menopause age. Past heritability estimates have not accounted for shared environment, and thus, the effect of genetic variants on menopause age may previously have been overestimated.

A strong clustering of Hodgkin lymphoma in certain families has been long acknowledged. However, the genetic factors in the background of familial Hodgkin lymphoma are largely unknown. We have studied a family of four cousins with a rare subtype of the disease, nodular lymphocyte predominant Hodgkin lymphoma. We applied exome sequencing together with genome-wide linkage analysis to this family and identified a truncating germline mutation in nuclear protein, ataxia-telangiectasia locus (NPAT) gene which segregated in the family. We also studied a large number of samples from other patients with Hodgkin lymphoma, and a germline variation leading to the deletion of serine 724 was found in several cases suggesting an elevated risk for the disease (odds ratio 4.11, P=0.018). NPAT is thus far the first gene implicated in NLPHL predisposition.

Since an association between the HLA region and Hodgkin lymphoma (HL) was first reported in 1967, many studies have reported associations between HL risk and both SNP and classical HLA allele variation in the Major Histocompatibility Complex (MHC). However, population stratification and the extent and complexity of linkage disequilibrium within the MHC have hindered efforts to fine-map causal signals. Using SNP data to impute alleles at classical HLA loci, we have conducted an integrated analysis of HL risk within the HLA region in 582 early-onset HL cases and 4,736 controls. We confirm that the strongest signal of association comes from a SNP located in the class II region, rs6903608 (OR = 1.79, P=6.63x10(-19)), which is unlikely to be driven by association to HLA-DRB, DQA, or DQB alleles. In addition, we identify independent signals at rs2281389 (OR=1.73, P=6.31x10(-13)), a SNP which maps closely to HLA-DPB1, and the class II HLA allele DQA1*02:01 (OR=0.56, P=1.51x10(-7)). These data suggest that multiple independent loci within the HLA class II region contribute to the risk of developing early-onset HL.

Morris DH, Jones ME, Schoemaker MJ, Ashworth A, Swerdlow AJ. Secular trends in age at menarche in women in the UK born 1908-93: results from the Breakthrough Generations Study. Paediatric and Perinatal Epidemiology 2011; 25: 394-400. Menarcheal age decreased over time in Western countries until cohorts born in the mid-20th century. It then stabilised, but limited data are available for recent cohorts. Menarche data were collected retrospectively by questionnaire in 2003-10 from 94 170 women who were participating in the Breakthrough Generations Study, aged 16-98 years, born 1908-93 and resident in the UK. Average menarcheal age declined from women born in 1908-19 (mean = 13.5 years) to those born in 1945-49 (mean = 12.6 years). It was then stable for several birth cohorts, but resumed its downward trend in recent cohorts (mean = 12.3 years in 1990-93 cohort). Trends differed between socio-economic groups, but the recent decline was present in each group. In conclusion, menarcheal age appears to have decreased again in recent cohorts after a period of stabilisation.

BACKGROUND: Despite extensive research on the topic, glioma etiology remains largely unknown. Exploration of potential interactions between single-nucleotide polymorphisms (SNPs) of immune genes is a promising new area of glioma research. The case-only study design is a powerful and efficient design for exploring possible multiplicative interactions between factors that are independent of one another. The purpose of our study was to use this exploratory design to identify potential pair wise SNP-SNP interactions from genes involved in several different immune-related pathways for investigation in future studies. METHODS: The study population consisted of two case groups: 1224 histological-confirmed, non-Hispanic white glioma cases from the U.S. and a validation population of 634 glioma cases from the U.K. Polytomous logistic regression, in which one SNP was coded as the outcome and the other SNP was included as the exposure, was utilized to calculate the odds ratios of the likelihood of cases simultaneously having the variant alleles of two different SNPs. Potential interactions were examined only between SNPs located in different genes or chromosomes. RESULTS: Using this data-mining strategy, we found 396 significant SNP-SNP interactions among polymorphisms of immune-related genes that were present in both the U.S. and U.K. study populations. CONCLUSIONS: This exploratory study was conducted for the purpose of hypothesis generation, and thus has provided several new hypotheses that can be tested using traditional case-control study designs to obtain estimates of risk.Impact:This is the first study, to our knowledge, to take this novel approach to identifying SNP-SNP interactions relevant to glioma etiology.

Although epidemiological studies have suggested an association between atopy and glioma risk, these observations have been based on self-reporting of allergic conditions raising the possibility that associations may be noncausal and arise as a consequence of bias, reverse causation or other artifacts. Genetic information provides an alternative approach to investigate the relationship avoiding such biases. We analyzed 1,878 glioma cases and 3,670 controls for variants at 2q12, 5q12.1, 11q13 and 17q21 that are associated with asthma or eczema risk at p < 5.0 × 10(-7) . The SNP rs7216389, which tags the 3' flanking region of ORMDL3 at 17q21 and has been associated with childhood asthma, was correlated with increased glioma risk (OR = 1.10; 95% CI: 1.01-1.19). These data provide evidence for a correlation between asthma susceptibility and glioma risk and illustrate the value of using genetics as an investigative tool for developing etiological hypotheses.

Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered.

While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P(c) = 7.72 × 10(-8) and 2.09 × 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk.

The energy absorbed from the radio-frequency fields of mobile telephones depends strongly on distance from the source. The authors' objective in this study was to evaluate whether gliomas occur preferentially in the areas of the brain having the highest radio-frequency exposure. The authors used 2 approaches: In a case-case analysis, tumor locations were compared with varying exposure levels; in a case-specular analysis, a hypothetical reference location was assigned for each glioma, and the distances from the actual and specular locations to the handset were compared. The study included 888 gliomas from 7 European countries (2000-2004), with tumor midpoints defined on a 3-dimensional grid based on radiologic images. The case-case analyses were carried out using unconditional logistic regression, whereas in the case-specular analysis, conditional logistic regression was used. In the case-case analyses, tumors were located closest to the source of exposure among never-regular and contralateral users, but not statistically significantly. In the case-specular analysis, the mean distances between exposure source and location were similar for cases and speculars. These results do not suggest that gliomas in mobile phone users are preferentially located in the parts of the brain with the highest radio-frequency fields from mobile phones.

Background:The rationale, design, recruitment and follow-up methods are described for the Breakthrough Generations Study, a UK cohort study started in 2003, targeted at investigation of breast cancer aetiology.Methods:Cohort members have been recruited by a participant referral method intended to assemble economically a large general population cohort from whom detailed questionnaire information and blood samples can be obtained repeatedly over decades, with high completeness of follow-up and inclusion of large numbers of related individuals. 'First-generation' recruits were women contacted directly, or who volunteered directly, to join the study. They nominated female friends and family, whom we contacted, and those who joined ('second generation') nominated others, reiterated for up to 28 generations.Results:The method has successfully been used during 2003-2011 to recruit 112 049 motivated participants with a broad geographic and socioeconomic distribution, aged 16-102 years, who have completed detailed questionnaires; 92% of the participants gave blood samples at recruitment. When eligible, 2½ years after recruitment, >98% completed the first follow-up questionnaire. Thirty percent are first-degree relatives of other study members.Conclusion:The 'generational' recruitment method has enabled recruitment of a large cohort who appear to have the commitment to enable long-term continuing data and sample collection, to investigate the effects of changing endogenous and exogenous factors on cancer risk.British Journal of Cancer advance online publication, 6 September 2011; doi:10.1038/bjc.2011.337 www.bjcancer.com.

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.

Infectious mononucleosis (IM) is common among university students. We undertook to analyze the clinical features and sequelae of the disease in a cohort of students at Edinburgh University.

Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.

The etiology of glioma is barely known. Epidemiologic studies have provided evidence for an inverse relation between glioma risk and allergic disease. Genome-wide association data have identified common genetic variants at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A-CDKN2B), 11q23.3 (rs498872, PHLDB1), and 20q13.33 (rs6010620, RTEL1) as determinants of glioma risk. The authors investigated whether there is interaction between the effects of allergy and these 5 variants on glioma risk. Data from 5 case-control studies carried out in Denmark, Finland, Sweden, and the United Kingdom (2000-2004) were used, totaling 1,029 cases and 1,668 controls. Risk was inversely associated with asthma, hay fever, eczema, and "any allergy," significantly for each factor except asthma, and was significantly positively associated with number of risk alleles for each of the 5 single nucleotide polymorphisms. There was interaction between asthma and rs498872 (greater protective effect of asthma with increasing number of risk alleles; per-allele interaction odds ratio (OR) = 0.65, P = 0.041), between "any allergy" and rs4977756 (smaller protective effect; interaction OR = 1.27, P = 0.047), and between "any allergy" and rs6010620 (greater protective effect; interaction OR = 0.70, P = 0.017). Case-only analyses provided further support for atopy interactions for rs4977756 and rs498872. This study provides evidence for possible gene-environment interactions in glioma development.

The population of the Semipalatinsk region of Kazakhstan was chronically exposed to radioactive fallout from above-ground nuclear tests conducted during 1949-1956 by the Soviet Union. We investigated the effect of radiation exposure and other factors on risks of twinning overall and of same- and different-sex twinning and hence estimated dizygotic and monozygotic twinning rates in 11,605 deliveries around Semipalatinsk, 141 of which were twin, to 3992 mothers exposed to fallout during 1949-1956. Overall, the same-sex twinning rate was 7.85 [95% confidence interval (CI): 6.24, 9.47] per 1000 and the opposite-sex twinning rate was 4.45 (95% CI: 3.23, 5.67). Twinning rates did not differ significantly between radiation exposure categories, parental age at main radiation exposure, or year of birth. Different-sex, but not same-sex, twinning increased with maternal age (P(trend) = 0.04) but not with other demographic factors and was increased soon after radiation exposure [OR = 4.08 (95% CI: 1.11, 15.07)] for births occurring within 5 years compared with more than 20 years after exposure; this effect was similar in villages with low and high radiation exposure, however, so interpretation is uncertain.

Methods An interview-based case-control study with 2708 glioma and 2409 meningioma cases and matched controls was conducted in 13 countries using a common protocol.Results A reduced odds ratio (OR) related to ever having been a regular mobile phone user was seen for glioma [OR 0.81; 95% confidence interval (CI) 0.70-0.94] and meningioma (OR 0.79; 95% CI 0.68-0.91), possibly reflecting participation bias or other methodological limitations. No elevated OR was observed >= 10 years after first phone use (glioma: OR 0.98; 95% CI 0.76-1.26; meningioma: OR 0.83; 95% CI 0.61-1.14). ORs were < 1.0 for all deciles of lifetime number of phone calls and nine deciles of cumulative call time. In the 10th decile of recalled cumulative call time, >= 1640 h, the OR was 1.40 (95% CI 1.03-1.89) for glioma, and 1.15 (95% CI 0.81-1.62) for meningioma; but there are implausible values of reported use in this group. ORs for glioma tended to be greater in the temporal lobe than in other lobes of the brain, but the CIs around the lobe-specific estimates were wide. ORs for glioma tended to be greater in subjects who reported usual phone use on the same side of the head as their tumour than on the opposite side.Conclusions Overall, no increase in risk of glioma or meningioma was observed with use of mobile phones. There were suggestions of an increased risk of glioma at the highest exposure levels, but biases and error prevent a causal interpretation. The possible effects of long-term heavy use of mobile phones require further investigation.

To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk.

Mobile phone use is now ubiquitous, and scientific reviews have recommended research into its relation to leukaemia risk, but no large studies have been conducted.

To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10(-8)), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10(-13)) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10(-8)). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10(-50)). These data provide new insight into the pathogenesis of cHL.

Early menarche increases breast cancer risk but, aside from weight, information on its determinants is limited.

P>The reciprocal familial risk between chronic lymphocytic leukaemia (CLL) and Hodgkin lymphoma (HL) suggests genetic variants with pleiotropic effects may influence the risk of both CLL and HL. We have recently shown that the IRF4 variant rs872071 influences CLL risk. To examine if rs872071 genotype is associated with HL risk we genotyped two case-control series (totalling, 529 and 2192, respectively). This analysis provides evidence that IRF4 rs872071 influences HL risk; Odds Ratio = 1 center dot 21 (95% confidence interval: 1 center dot 05-1 center dot 39, P = 0 center dot 009) and highlights the importance of inherited variation in B-cell developmental genes in the development of HL.

A large number of melanocytic nevi is the strongest known risk factor for melanoma in whites, but its relationship to sun exposure overseas among young white women living in temperate climates is unclear. A total of 754 white English women aged 18-46 years were recruited into a cross-sectional study in 1997-2000 to investigate the effect of ultraviolet exposures on numbers of nevi and atypical nevi, and on skin aging as measured by microtopography. Having ever holidayed in hotter countries was associated with a greater age- and phenotype-adjusted mean number of whole-body nevi (percent increase=74; 95% confidence interval: 24, 144; P=0.001), particularly for holidays taken at ages 18-29 years and for counts of the trunk and lower limbs. Having ever lived overseas was not associated with nevus counts, but was inversely associated with number of atypical nevi (P=0.02). Skin aging was not associated with residence or holidays abroad. The association of holidays overseas with an increased nevus count in young white women, which was stronger in the anatomical sites intermittently exposed to sunlight, supports the hypothesis that intermittent sun exposure is of relevance in the etiology of nevi and, hence, melanoma. The findings are of public health relevance given the growing popularity of foreign holidays.

An abnormal nevus phenotype is associated with an increased risk of melanoma. We report a pooled analysis conducted using individual nevus data from 15 case-control studies (5,421 melanoma cases and 6,966 controls). The aims were to quantify the risk better and to determine whether relative risk is varied by latitude. Bayesian unconditional logistic random coefficients models were employed to study the risk associated with nevus characteristics. Participants with whole body nevus counts in the highest of 4 population-based categories had a greatly increased risk of melanoma compared with those in the lowest category (pooled odds ratio (pOR) 6.9 (95% confidence interval (CI): 4.4, 11.2) for those aged<50 years and pOR 5.1 (95% CI: 3.6, 7.5) for those aged>or=50). The pOR for presence compared with absence of any clinically atypical nevi was 4.0 (95% CI: 2.8, 5.8). The pORs for 1-2 and >or=3 large nevi on the body compared with none were 2.9 (95% CI: 1.9, 4.3) and 7.1 (95% CI: 4.7, 11.6), respectively. The relative heterogeneities among studies were small for most measures of nevus phenotype, except for the analysis of nevus counts on the arms, which may have been due to methodological differences among studies. The pooled analysis also suggested that an abnormal nevus phenotype is associated most with melanomas on intermittently sun-exposed sites. The presence of increased numbers of nevi, large nevi and clinically atypical nevi on the body are robust risk factors for melanoma showing little variation in relative risk among studies performed at different latitudes.

A "divergent pathway" model for the development of cutaneous melanoma has been proposed. The model hypothesizes that melanomas occurring in people with a low tendency to develop nevi will, on average, arise more commonly on habitually sun-exposed body sites such as the head and neck. In contrast, people with an inherent propensity to develop nevi will tend to develop melanomas most often on body sites with large melanocyte populations, such as on the back. We conducted a collaborative analysis to test this hypothesis using the original data from 10 case-control studies of melanoma in women (2,406 cases and 3,119 controls), with assessment of the potential confounding effects of socioeconomic, pigmentary and sun exposure-related factors. Higher nevus count on the arm was associated specifically with an increased risk of melanoma of the trunk (p for trend = 0.0004) and limbs (both upper and lower limb p for trends = 0.01), but not of the head and neck (p for trend = 0.25). The pooled odds ratios for the highest quartile of nonzero nevus count versus none were 4.6 (95% confidence interval (CI) 2.7-7.6) for melanoma of the trunk, 2.0 (95% CI 0.9-4.5) for the head and neck, 4.2 (95% CI 2.3-7.5) for the upper limbs and 3.4 (95% CI 1.5-7.9) for the lower limbs. Aggregate data from these studies suggest that high nevus counts are strongly associated with melanoma of the trunk but less so if at all of the head and neck. This finding supports different etiologic pathways of melanoma development by anatomic site.

The use of screening episodes linked to CIN3 and invasive cancer registrations to study outcomes from the NHS Cervical Screening ProgrammeObjective: To examine how NHS cervical screening data can be collected and analysed in order to evaluate women's screening histories as episodes rather than as individual smears. Design: Analysis of routine cervical screening data grouped into screening episodes for a cohort of women regarding episodes starting in a given year. Setting: NHS Cervical Screening Programme. Population: Data from four Health Authorities (now eight Primary Care Trusts) from the NHS Cervical Screening Programme with primary smears (first in an episode) taken between 1 April 1999 and 31 March 2000. Methods: Cytology information obtained from the call/recall ('Exeter') computer system was linked to cervical intraepithelial neoplasia (CIN) 3 and invasive cancer outcome information obtained from cancer registries. Screening histories were divided into episodes, each starting with a primary smear that was followed up to episode closure or, for episodes still open followed for an average 4.25 years, from the primary smear. The episode was divided into two parts (up to referral to colposcopy and following the referral). The outcomes of the episodes are described including referral rate to colposcopy and CIN3 and invasive cancer rates by factors such as age. Main outcome measures: Episode histories and rates of referral to colposcopy, CIN3 and invasive cancer. Results: There were 176 923 episodes from 176 319 women (1.003 episodes per woman) followed up to March 2004, the date at which the first phase of information accrual ceased. Of these episodes, 172 100 (97.3%) were closed either by a negative smear referring the woman back to routine recall or by default (defined as no smear recorded within 21 months following a smear requiring an action of repeat or refer to colposcopy). The remaining 4823 (2.7%) of episodes were still open, of which in 3121 (1.8%) the woman had been referred to colposcopy and in 1702 (1.0%) no referral decision had been made. Referral rates to colposcopy varied by age from 5.7% in women aged 20-24 years down to 0.9% in women aged 60-64 years. The overall efficiency of screening was highest for woman aged about 30 years, with a CIN3 detection rate of eight per 1000 women and a positive predictive value (for CIN3 or worse) of referral to colposcopy of 21%. Conclusion: The study has shown that routinely collected NHS cervical screening data can be combined to give information on complete episodes, allowing important performance measures to be studied. We suggest that in future information in the NHS screening system should be structured to facilitate such analysis and to allow cytology and histology information to be readily linked.

There is public concern and scientific interest regarding a potential effect of cellular phone use on the risk of developing intracranial tumors. Tumors of the pituitary gland have barely been investigated in this context, but are of interest because of their intracranial location.

Melanoma risk is related to sun exposure; we have investigated risk variation by tumour site and latitude.

There is discussion over the benefit of continuing cervical screening in women over the age of 50 with a history of negative cytology. We aimed to determine the risk of abnormal cytology in such women. Screening history data from 1985 to 2003 were obtained for a cohort of 2 million women from the NHS cervical screening programme from four Health Authorities in England. The 57,651 women in the cohort who reached age 40 between 1 January 1985 and 31 December 1990 and had at least one routine or opportunistic smear between ages 50 and 54 were included in the analysis. Exposure groups (negative cytology history, negative but including inadequate smears, and positive history) were defined on the basis of screening histories from ages 40 to 49. Sixty-four percent (134/206) (95% CI: 57-71%) of the moderate dyskaryosis or worse lesions at ages over 50 were detected from women in the negative smear history group. After allowance for time since last negative smear, the relative risk for the first primary smear over the age of 50 having moderate dyskaryosis or worse decreased from 0.60 (95% CI: 0.41-0.84) for two negative smear episodes to 0.25 (95% CI: 0.10-0.56) for four negative smear episodes, compared with the positive history group. If screening were discontinued for all women over 50 with a negative history, the majority of cytological abnormalities now being detected at these ages that lead directly to referral to colposcopy would be missed.

Pituitary gland tumors are usually benign but are associated with substantial morbidity. Their etiology is largely unknown. We conducted a population-based case-control study of potential risk factors for pituitary tumors in Southeast England. Information on medical and reproductive history, female sex hormones, and cigarette smoking was collected by personal interview from 299 cases and 630 controls aged 18 to 59 years. Tumor risk was reduced in subjects reporting a past diagnosis of hay fever [odds ratio (OR), 0.7; 95% confidence interval (CI), 0.5-1.0] but not asthma or eczema. Risk was raised in women who were postmenopausal 1 year before diagnosis (OR, 3.2; 95% CI, 1.6-6.2), especially if menopause was surgically induced (OR, 6.7; 95% CI, 2.2-19.9) or occurred under age 40 years (OR, 7.5; 95% CI, 2.6-21.4). This effect remained when evaluating menopausal status 10 years before diagnosis. There was no association with parity overall, but risk was increased for first childbirth under age 20 years compared with nulliparity (OR, 3.4; 95% CI, 1.4-8.4). No significant association was observed with ever use of oral contraceptives or hormone replacement therapy, nor with cigarette smoking, past head injury, past diagnosis with epilepsy, or birth characteristics, except for an inverse association of risk with maternal age. This study suggests a raised risk of pituitary tumors in relation to surgically induced menopause, early postmenopausal age, and young age at childbirth, and possibly a reduced risk with hay fever and increasing maternal age. Reasons for these associations need further investigation, but some associations might be due to hormonal effects of an undiagnosed pituitary tumor.

This review summarizes and interprets epidemiologic evidence bearing on a possible causal relation between radiofrequency field exposure from mobile phone use and tumor risk. In the last few years, epidemiologic evidence on mobile phone use and the risk of brain and other tumors of the head in adults has grown in volume, geographic diversity of study settings, and the amount of data on longer-term users. However, some key methodologic problems remain, particularly with regard to selective nonresponse and inaccuracy and bias in recall of phone use. Most studies of glioma show small increased or decreased risks among users, although a subset of studies show appreciably elevated risks. We considered methodologic features that might explain the deviant results, but found no clear explanation. Overall the studies published to date do not demonstrate an increased risk within approximately 10 years of use for any tumor of the brain or any other head tumor. Despite the methodologic shortcomings and the limited data on long latency and long-term use, the available data do not suggest a causal association between mobile phone use and fast-growing tumors such as malignant glioma in adults (at least for tumors with short induction periods). For slow-growing tumors such as meningioma and acoustic neuroma, as well as for glioma among long-term users, the absence of association reported thus far is less conclusive because the observation period has been too short.

Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.

To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations.

We have carried out melanoma case-control comparisons for six vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) and serum 25-hydroxyvitamin D-3 levels in order to investigate the role of vitamin D in melanoma susceptibility. There was no significant evidence of an association between any VDR SNP and risk in 1028 population-ascertained cases and 402 controls from Leeds, UK. In a second Leeds case-control study (299 cases and S60 controls) the FokI T allele was associated with increased melanoma risk (odds ratio (OR) 1.42, 95% confidence interval (CI) 1.06-1.91, p = 0.02). In a meta-analysis in conjunction with published data from other smaller data sets (total 3769 cases and 3636 controls), the FokI T allele was associated with increased melanoma risk (OR 1.19, 95% CI 1.05-1.35), and the BsmI A allele was associated with a reduced risk (OR 0.81, 95% Cl 0.72-0.92), in each instance under a parsimonious dominant model. In the first Leeds case-control comparison cases were more likely to have a higher body mass index (BMI) than controls (p = 0.007 for linear trend). There was no evidence of a case-control difference in serum 25-hydroxyvitamin D-3 levels. In 1043 incident cases from the first Leeds case-control study, a single estimation of serum 25-hydroxyvitamin D-3 level taken at recruitment was inversely correlated with Breslow thickness (p = 0.03 for linear trend). These data provide evidence to support the view that vitamin D and VDR may have a small but potentially important role in melanoma susceptibility, and putatively a greater role in disease progression. (C) 2009 Elsevier Ltd. All rights reserved.

Anthropometric factors such as height, weight and body mass index are related to the occurrence of certain malignancies in women including cancers of the breast, ovary and endometrium. Several studies have investigated the relation between height and weight or body mass and the risk of cutaneous melanoma in women, but results have been inconsistent. We conducted a collaborative analysis of these factors using the original data from 8 case-control studies of melanoma in women (2,083 cases and 2,782 controls), with assessment of the potential confounding effects of socioeconomic, pigmentary and sun exposure-related factors. Women in the highest quartile of height had an increased risk of melanoma [pooled odds ratio (pOR) 1.3, 95% confidence interval (CI) 1.1-1.6]. We also found an elevated risk associated with weight gain in adult life of 2 kg or more (pOR 1.5, 95% CI 1.1-2.0). Stratifying by age at melanoma diagnosis (<50, >or=50 yr), we found this risk greater among women <50 yr of age. Associations were unaffected by adjustment for other known risk factors for melanoma. There was no evidence that the effects varied for different histologic subtypes of cutaneous melanoma. There was no association with body weight per se, body mass index, or body surface area, either recent or in young adulthood. In aggregate, data from these studies suggest that greater height and weight gain may be risk factors for cutaneous melanoma in women.

Constitutional chromosome deletions result in wide ranging morbidity and often fatality. Information about risks and causes of death in these patients is important for counselling, and may illuminate the functions of the part of the chromosome deleted. There have been no cohort studies analysing mortality risks in persons with specific deletions compared with general population rates. We therefore conducted a cohort study following cause-specific mortality in 2,561 patients with autosomal chromosome deletions diagnosed by light microscopy or fluorescence in situ hybridisation at cytogenetic laboratories across Britain, 1965-2002. The commonest deletions were of 22q (544 patients), 15q (460) and 7q (210) and the least common 19q (0) and 20q (2). The prevalence of visible deletions of different chromosome arms was significantly inversely correlated with gene density of the arm (p < 0.001). Mortality was 11-fold raised in the cohort compared with the general population (standardised mortality ratio = 11.4 (95% confidence interval 10.0-12.8)), was significantly raised for each deletion with > or = 25 subjects in the study, and had a lower confidence limit > 10 for deletions of 1p, 1q, 3p, 4p, 5q and 22q. Overall, 29% of deaths were due to congenital anomalies; significantly raised mortality occurred also from many other causes, varying by chromosome and arm of deletion. The data imply that viability of foetuses with visible chromosome deletions may be inversely related to gene density, and that all visible and fluorescence in situ hybridisation-detectable deletions lead to much raised mortality, but the extent and causes of mortality vary according to the specific deletion.

Turner syndrome, one of the most common cytogenetic abnormalities, is characterised by complete or partial X-chromosome monosomy. Cancer risks in women with Turner syndrome have not been clearly established. We aimed to compare the risk of cancer in women with this syndrome with that of the general population.

Several single nucleotide polymorphisms (SNPs) affecting DNA repair capacity and modifying cancer susceptibility have been described. We evaluated the association of SNPs Arg194Trp, Arg280His, and Arg399Gln in the X-ray cross-complementing group 1 (XRCC1) and Thr241Met in the X-ray cross-complementing group 3 (XRCC3) DNA repair genes with the risk of brain tumors. The Caucasian study population consisted of 701 glioma (including 320 glioblastoma) cases, 524 meningioma cases, and 1,560 controls in a prospective population-based case-control study conducted in Denmark, Finland, Sweden, and the UK. The studied SNPs were not significantly associated with the risk of brain tumors. The highest odds ratios (ORs) for the associations were observed between the homozygous variant genotype XRCC1 Gln399Gln and the risk of glioma (OR = 1.32; 95% confidence interval, CI, 0.97-1.81), glioblastoma (OR = 1.48; 95% CI, 0.98-2.24), and meningioma (OR = 1.34; 95% CI, 0.96-1.86). However, in pair-wise comparisons a few SNP combinations were associated with the risk of brain tumors: Among others, carriers of both homozygous variant genotypes, i.e., XRCC1 Gln399Gln and XRCC3 Met241Met, were associated with a three-fold increased risk of glioma (OR = 3.18; 95% CI, 1.26-8.04) and meningioma (OR = 2.99; 95% CI, 1.16-7.72). In conclusion, no significant association with brain tumors was found for any of the polymorphisms, when examined one by one. Our results indicated possible associations between combinations of XRCC1 and XRCC3 SNPs and the risk of brain tumors.

The finding of increased risks of specific cancers in individuals with constitutional deletions of chromosomes 11p and 13q led to the discovery of cancer predisposition genes at these locations, but there have been no systematic studies of cancer risks in patients with constitutional deletions, across the chromosome complement. Therefore, we assessed cancer incidence in comparison with national cancer incidence rates in a follow-up of 2561 patients with constitutional autosomal chromosome deletions diagnosed by microscopy or fluorescence in situ hybridisation in Britain during the period 1965-2002. Thirty cancers other than non-melanoma skin cancer occurred in the cohort (standardised incidence ratio (SIR)=2.4, 95% confidence interval (CI) 1.6-3.5). There were significantly increased risks of renal cancer in persons with 11p deletions (SIR=1869, 95% CI 751-3850; P=4 x 10(-21)), eye cancer with 13q deletions (SIR=1084, 95% CI 295-2775; P=2 x 10(-11)), and anogenital cancer with 11q deletions (SIR=305, 95% CI 63-890; P=3 x 10(-7)); all the three latter cancers were in the 11 subjects with 11q24 deletions. The results strongly suggest that in addition to suppressor genes relating to Wilms' tumour risk on 11p and retinoblastoma on 13q, there are suppressor genes around 11q24 that greatly affect anogenital cancer risk.

Use of mobile telephones has been suggested as a possible risk factor for intracranial tumours. To evaluate the effect of mobile phones on risk of meningioma, we carried out an international, collaborative case-control study of 1209 meningioma cases and 3299 population-based controls.

Turner syndrome is characterized by complete or partial X chromosome monosomy. It is associated with substantial morbidity, but mortality risks and causes of death are not well described.

Female sex hormones have previously been suggested as possible risk factors for brain tumors, but published studies have reported conflicting results. We conducted a population-based case-control study of glioma (n=626) and meningioma (n=906) cases and randomly selected controls stratified on age and geographic region (n=1,774) in Denmark, Finland, Norway, Sweden, and the United Kingdom. Unconditional logistic regression was used to estimate odds ratios (OR) for glioma and meningioma in relation to reproductive factors. A decreased glioma risk was associated with ever-pregnancy compared with never-pregnancy [OR, 0.8; 95% confidence interval (95% CI), 0.6-1.0]. Meningioma risk among women ages <50 years was increased in relation to number of pregnancies leading to a live birth (OR, 1.8; 95% CI: 1.1-2.8 for giving birth to 3 children compared with nulliparous women; P(trend) among parous women=0.01). This relation was not found for older women. Breast-feeding among parous women increased the glioma risk (OR, 2.2; 95% CI, 1.3-3.9 for breast-feeding 36 months or more compared with breast-feeding 3 months or less). Menopausal status and age at menopause were not associated with meningioma or glioma risk. Our findings imply that reproductive hormones may influence the occurrence of meningioma and glioma.

Much of the variation in inherited risk of glioma is likely to be explained by combinations of common low risk variants. The established relationship between glioma risk and exposure to ionizing radiation led us to examine whether variants in the DNA repair genes contribute to disease susceptibility. We evaluated 1127 haplotype-tagging single-nucleotide polymorphisms (SNPs) supplemented with 388 putative functional SNPs to capture most of the common variation in 136 DNA repair genes, in five unique case-control series from four different countries (1013 cases, 1016 controls). We identified 16 SNPs associated with glioma risk at the 1% significance level. The highest association observed across the five independent case-control datasets involved rs243356, which maps to intron 3 of CHAF1A (trend odds ratio, 1.32; 95% confidence interval 1.14-1.54; P = 0.0002; false-positive report probability = 0.055, based on a prior probability of 0.01). Our results provide additional support for the hypothesis that low penetrance variants contribute to the risk of developing glioma and suggest that a genetic variant located in or around the CHAF1A gene contributes to disease risk.

Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility.

Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor.

Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk.

Time spent in transit may affect the concentration of various constituents of collected blood samples and, consequently, results of sex hormone assays. Whole blood was collected from 46 women, and one third was processed immediately, one third was stored at ambient conditions (22 degrees C) for 1 day, and one third was stored for 2 days. Estradiol concentration increased by 7.1% [95% confidence interval (95% CI), 3.2-11.3%] after a delay in processing of 1 day and by 5.6% (95% CI, 0.2-11.4%) after a delay in processing of 2 days; the change was most apparent at lower than median concentrations. Progesterone concentrations showed no substantial change. Testosterone concentrations changed by 23.9% (95% CI, 17.8-30.3%) after a delay of 1 day but little thereafter. The sex hormone-binding globulin concentration decreased by 6.6% (95% CI, 4.6-8.6%) and 10.9% (95% CI, 8.1-13.6%), follicle-stimulating hormone increased by 7.4% (95% CI, 4.2-10.7%) and 13.9% (95% CI, 8.7-19.3%), and luteinizing hormone increased by 4.9% (95% CI, 1.3-8.5%) and 6.7% (95% CI, 2.2-11.5%) after a delay in processing of 1 and 2 days. Increases in calculated values for biologically available levels of estradiol and testosterone were greater than the increases seen in measured total hormone concentrations. Similar changes are likely when samples are delayed in transit, and evidence of etiology may be obscured unless study designs or analyses take into account processing delays.

Acoustic neuroma (vestibular schwannoma) is a benign tumor of the vestibulocochlear nerve. Its recorded incidence is increasing but risk factors for this tumor have scarcely been investigated. We conducted a population-based case-control study of risk factors for acoustic neuroma in the UK and Nordic countries, including 563 cases and 2,703 controls. Tumor risk was analyzed in relation to medical history and cigarette smoking. Risk of acoustic neuroma was significantly raised in parous compared with nulliparous women (OR = 1.7, 95% CI: 1.1-2.6), but was not related to age at first birth or number of children. Risk was not associated with a history of allergic disease, past head injury, past diagnosis of a neoplasm or birth characteristics, but was significantly raised for past diagnosis of epilepsy (OR = 2.5, 95% CI: 1.3-4.9). Tumor risk was significantly reduced in subjects who had ever regularly smoked cigarettes (OR = 0.7, 95% CI: 0.6-0.9), but the reduction applied only to current smokers (OR = 0.5, 95% CI: 0.4-0.6), not ex-smokers (OR = 1.0, 95% CI: 0.8-1.3). The reduced risk of acoustic neuroma in smokers and raised risk in parous women might relate to sex hormone levels, or smoking might suppress tumor growth, but effects of parity and smoking on timing of diagnosis of the tumor are also a potential explanation. The raised risk in relation to past diagnosis of epilepsy might be a surveillance artefact or imply that epilepsy and/or antiepileptic medication use predispose to acoustic neuroma. These findings need replication by other studies and possible mechanisms need to be clarified.

P53 and ATM are central checkpoint genes involved in the repair of DNA damage after ionising irradiation, which has been associated with risk of brain tumours. Therefore, we tested the hypothesis that polymorphisms and haplotypes in p53 and ATM could be associated with glioma and meningioma risk.

Epidemiologic studies have consistently shown inverse associations of allergic disease with risk of glioma, but it is unclear whether this association also applies to meningioma. The authors conducted a pooled analysis of meningioma risk in relation to a history of allergic disease based on data from two population-based, case-control studies with 475 cases and 1,716 controls in the United Kingdom (2001-2004). Meningioma risk was significantly reduced in relation to self-reported, physician-diagnosed allergic disease (odds ratio = 0.76, 95% confidence interval (CI): 0.61, 0.96) but was nonsignificantly reduced for individual conditions: asthma (odds ratio = 0.85, 95% CI: 0.61, 1.18), hay fever (odds ratio = 0.81, 95% CI: 0.62, 1.06), and eczema (odds ratio = 0.72, 95% CI: 0.51, 1.02). Risk reductions were greatest for asthma (odds ratio = 0.43, 95% CI: 0.21, 0.89) and hay fever (odds ratio = 0.50, 95% CI: 0.25, 1.00) with an early age at onset (<10 years) and for eczema (odds ratio = 0.46, 95% CI: 0.21, 1.07) with an onset at ages 10-19 years; they were near unity for onset in adulthood. This study suggests an inverse association between a history of allergies and meningioma risk, but with smaller risk reductions than for glioma. The reasons for this association need clarification, as well as an etiologic explanation. Consideration also needs to be given to confounding or bias.

Risk factors for primary infection with Epstein-Barr virus (EBV) and its subtypes have not been fully investigated.

Public concern has been expressed about the possible adverse health effects of mobile telephones, mainly related to intracranial tumors. We conducted a population-based case-control study to investigate the relationship between mobile phone use and risk of glioma among 1,522 glioma patients and 3,301 controls. We found no evidence of increased risk of glioma related to regular mobile phone use (odds ratio, OR = 0.78, 95% confidence interval, CI: 0.68, 0.91). No significant association was found across categories with duration of use, years since first use, cumulative number of calls or cumulative hours of use. When the linear trend was examined, the OR for cumulative hours of mobile phone use was 1.006 (1.002, 1.010) per 100 hr, but no such relationship was found for the years of use or the number of calls. We found no increased risks when analogue and digital phones were analyzed separately. For more than 10 years of mobile phone use reported on the side of the head where the tumor was located, an increased OR of borderline statistical significance (OR = 1.39, 95% CI 1.01, 1.92, p trend 0.04) was found, whereas similar use on the opposite side of the head resulted in an OR of 0.98 (95% CI 0.71, 1.37). Although our results overall do not indicate an increased risk of glioma in relation to mobile phone use, the possible risk in the most heavily exposed part of the brain with long-term use needs to be explored further before firm conclusions can be drawn.

Myocardial infarction is a major cause of excess long-term mortality in survivors of Hodgkin disease, but limited information exists on the effects of specific chemotherapy regimens used to treat these patients on their risk of death from myocardial infarction.

As tamoxifen stimulates ovarian steroidogenesis in premenopausal women, induces ovulation and increases the incidence of benign ovarian cysts, there has been concern that it might also increase ovarian cancer risk in women treated premenopausally. In a national case-control study in Britain, treatment histories were collected for 158 cases of ovarian cancer after breast cancer diagnosed at ages under 55 years and 464 controls who had breast cancer at these ages without subsequent ovarian cancer. Risk of ovarian cancer was not raised for women overall who had taken tamoxifen (odds ratio (OR)=0.9, 95% confidence interval (CI) 0.6-1.3) or for those treated when premenopausal (OR=1.0, 95% CI 0.6-1.6) or perimenopausal (OR=0.7, 95% CI 0.2-2.4). There was also no relation of risk to daily dose, duration or cumulative dose of tamoxifen, or time since last use. There was, however, a significantly raised risk in relation to non-hormonal chemotherapy. The results suggest that tamoxifen treatment of premenopausal or perimenopausal women does not materially affect ovarian cancer risk, but that non-hormonal chemotherapy might increase risk.

Glutathione transferases (GST) detoxify environmental and endogenous compounds and levels of two polymorphic GST proteins, GSTM3 and GSTP1, are high in the brain. Previous studies of GSTM3 and GSTP1 polymorphisms and adult brain tumor risk have produced inconsistent results, whereas the GSTM3 -63 variant is newly identified and, therefore, has not yet been studied in this context. We therefore examined associations between GSTM3 -63, GSTM3 *A/*B, GSTP1 105, and GSTP1 114 variants and adult brain tumor risk and the interaction of the effects of these same polymorphisms with cigarette smoking. In addition, the enzymes NQO1 and CYP1A1 alter susceptibility to oxidative brain damage. Because there is less previous evidence for a role of NQO1, CYP1A1, GSTM1, and GSTT1 variants, we restricted analysis of these variants to a small preliminary study.

The mortality and cancer incidence risks among males with Y polysomy are unknown because there have been no large long-term cohort studies carried out of such men. We conducted a cohort study of 667 men diagnosed with the abnormality in Britain since 1959 to compare their mortality and cancer incidence rates with those of the general population. Sixty deaths occurred during follow-up to December 2005, twice the number expected from general population rates (standardised mortality ratio (SMR) = 2.0 (95% confidence interval (CI) 1.5-2.6)). Significantly raised mortality was observed for diseases of the nervous system (SMR = 7.0, 95% CI: 2.3-16.4), circulatory system (SMR = 2.1, 95% CI: 1.3-3.2), respiratory system (SMR = 4.0, 95% CI: 1.8-7.5), genitourinary system (SMR = 10.2, 95% CI: 1.2-36.9), and congenital anomalies (SMR = 11.9, 95% CI: 3.2-30.5). Four of the five nervous system deaths were from epilepsy, the risk of death from this condition being more than 20-fold raised. The rates of cancer incidence and mortality among these men was not significantly different from those in the general population. This study provides evidence that mortality rates from several specific causes are raised among men with Y polysomy. The use of these data in genetic counselling should be cautious particularly for cases of Y polysomy that are detected prenatally. Further investigations are required to confirm these findings and to elucidate the possible role of genes on the Y chromosome in the aetiology of these causes of death.

We present the results of a multicenter clinical trial using Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) generated from EBV-seropositive blood donors to treat patients with EBV-positive posttransplantation lymphoproliferative disease (PTLD) on the basis of the best HLA match and specific in vitro cytotoxicity. Thirty-three PTLD patients who had failed on conventional therapy were enrolled. No adverse effects of CTL infusions were observed and the response rate (complete or partial) in 33 patients was 64% at 5 weeks and 52% at 6 months. Fourteen patients achieved a complete remission, 3 showed a partial response, and 16 had no response at 6 months (5 died before completing treatment). At 5 weeks, there was a significant trend toward better responses with higher numbers of CD4(+) cells in infused CTL lines (P = .001) that were maintained at 6 months (P = .001). Patients receiving CTLs with closer HLA matching responded better at 6 months (P = .048). Female patients responded better than male patients, but the differences were not statistically significant. Our results show that allogeneic CTLs are a safe and rapid therapy for PTLD, bypassing the need to grow CTLs for individual patients. The response rate in this poor prognosis patient group is encouraging.

An inverse association between allergic conditions and glioma risk has been reported previously. In this large population-based case-control study, the authors identified cases diagnosed with glioma or meningioma in Denmark, Norway, Finland, Sweden, and southeast England between 2000 and 2004. Detailed information on self-reported physician-diagnosed allergic conditions was collected from 1,527 glioma cases, 1,210 meningioma cases, and 3,309 randomly selected controls. Logistic regression showed an odds ratio of 0.70 (95% confidence interval: 0.61, 0.80) for glioma associated with a diagnosis of any of asthma, hay fever, eczema, or other type of allergy. The risk estimates for glioma were around 0.65 for each allergic condition (asthma, eczema, hay fever, and food allergy), and the 95% confidence intervals were equally consistent, at around 0.55, 0.80. The reduced risks of glioma related to eczema, hay fever, and allergy overall, but not asthma, were confined to current rather than past conditions. Meningioma risk was not associated with allergic conditions, except for eczema (odds ratio = 0.74, 95% confidence interval: 0.60, 0.91). Our results show a reduced risk for glioma associated primarily with current allergic conditions. If this is etiologic, it has implications for the understanding of how allergic conditions might reduce the tumor risk.

The objective of this study was to study the prevalence of opportunistic smear taking in the NHS cervical screening programme between 1999 and 2003 and the relationship of this to screening interval policy.

The former Soviet Union conducted a nuclear test program in the Semipalatinsk region of northeastern Kazakhstan in 1949-1989. The population in the vicinity of the test site was chronically exposed to radiation fallout, especially from above-ground tests during 1949-1956. Male:female sex ratio has been proposed as a measure of reproductive health, with some reports suggesting an alteration in the sex ratio of offspring of parents exposed to radiation. We investigated the impact of radiation exposure and other factors on the sex ratio in the population inhabiting the exposed region. A total of 11,464 singleton births of 3,992 mothers exposed to radiation during 1949-1956 were analyzed. The overall sex ratio was 1.07, similar to the current sex ratio in Kazakhstan (1.06). The sex ratio increased from 1.04 where mothers received <20.0 cSv to 1.12 where mothers received > or =60.0 cSv. However, the linear trend across exposures was not significant (P = 0.42). No consistent association was found between the sex ratio and the time since parental radiation exposure, parental age at exposure, or year of birth. Sex ratio was significantly associated with maternal age, birth order and possibly ethnicity but not with paternal age, parental educational level or season. In conclusion, no significant association was found between radiation exposure level and sex ratio, but some previously suggested demographic factors were positively associated with sex ratio.

Previous studies found that allergies are inversely related to risk of glioma. In an earlier publication, using data from a Swedish case-control study, Schwartzbaum et al. report an inverse relation between risk of glioblastoma and four single nucleotide polymorphisms (SNP) on two genes [interleukin (IL)-4Ralpha, IL-13] that are associated with allergies. In addition, recent studies suggest that IL-4 and IL-13 induce cyclooxygenase-2 (COX-2) to resolve brain inflammation. To see whether previous Swedish results (110 cases, 430 controls) would be replicated, we estimated the association between glioblastoma and two IL-4Ralpha (rs1805015, rs1801275) and two IL-13 (rs20541, rs1800925) SNPs and their haplotypes and one COX-2 SNP (-765GC) using additional English, Danish, and Finnish data (217 cases, 1,171 controls). Among general population controls, we evaluated associations between these haplotypes, the COX-2 SNP, and self-reported allergies. Our data did not support our original observations relating individual IL-4Ralpha, IL-13, or COX-2 SNPs to glioblastoma risk. However, the T-G IL-4Ralpha haplotype was associated with glioblastoma risk (odds ratio, 2.26; 95% confidence interval, 1.13-4.52) and there was a suggestion of an inverse relation between this haplotype and hayfever prevalence among controls (odds ratio, 0.38; 95% confidence interval, 0.14-1.03). The lack of support for a link between four IL-4Ralpha and IL-13 SNPs and glioblastoma may reflect the absence of associations or may result from uncontrolled confounding by haplotypes related both to those that we examined and glioblastoma. Nonetheless, the association between the T-G IL-4Ralpha haplotype and glioblastoma risk may indicate a role of immune factors in glioblastoma development.

The very rapid worldwide increase in mobile phone use in the last decade has generated considerable interest in the possible health effects of exposure to radio frequency (RF) fields. A multinational case-control study, INTERPHONE, was set-up to investigate whether mobile phone use increases the risk of cancer and, more specifically, whether the RF fields emitted by mobile phones are carcinogenic. The study focused on tumours arising in the tissues most exposed to RF fields from mobile phones: glioma, meningioma, acoustic neurinoma and parotid gland tumours. In addition to a detailed history of mobile phone use, information was collected on a number of known and potential risk factors for these tumours. The study was conducted in 13 countries. Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden, and the UK using a common core protocol. This paper describes the study design and methods and the main characteristics of the study population. INTERPHONE is the largest case-control study to date investigating risks related to mobile phone use and to other potential risk factors for the tumours of interest and includes 2,765 glioma, 2,425 meningioma, 1,121 acoustic neurinoma, 109 malignant parotid gland tumour cases and 7,658 controls. Particular attention was paid to estimating the amount and direction of potential recall and participation biases and their impact on the study results.

There is evidence that pregnancy history including age at first birth and parity may play a role in risk of cutaneous melanoma in women, although, epidemiological findings are inconsistent. We conducted a collaborative analysis of these factors using the original data from ten completed case-control studies (2391 cases and 3199 controls), and assessed the potential confounding effects of socioeconomic, pigmentary, and sun exposure-related factors. We found no overall association with ever having a live birth (pooled odds ratio (pOR) 0.95, 95% confidence interval (CI) 0.67-1.35). However, we detected a reduced risk of melanoma among women with higher parity (> or = 5 versus no live births pOR 0.76, 95% CI 0.49-1.18, each live birth pOR 0.95, 95% CI 0.91-0.99, p trend = 0.05). Women with both earlier age at first birth (e.g., <20 years) and higher parity (e.g., > or = 5 live births) had a particularly lower risk than women with later age at first birth (e.g., > or = 25 years) and lower parity (e.g., <5 live births) (pOR 0.33, 95% CI 0.14-0.75). The results are compatible with an effect of reproductive history-related factors on melanoma risk, but also could reflect differences in other factors, such as sun exposure history.

To investigate the risk of glioma in adults in relation to mobile phone use.

To assess long-term site-specific risks of second malignancy following non-Hodgkin's lymphoma (NHL) in relation to treatment and demographic factors.

A vaccine against Epstein-Barr virus (EBV) infection is in clinical trials. Up-to-date information on risk factors for EBV infection and infectious mononucleosis (IM) among young adults is required to inform a vaccination strategy.

Epidemiological studies have consistently reported an inverse association between a history of allergic disease and risk of glioma. The reason for this association is unclear, and there is a lack of studies with the detail and size to explore the association in depth. We conducted a UK population-based case-control study with 965 glioma cases and 1,716 controls to investigate glioma risk in relation to allergic disease. Risk was reduced in subjects reporting a history of asthma (odds ratio (OR) = 0.71, 95% confidence interval (CI): 0.54-0.92), hay fever (OR = 0.73, 95% CI: 0.59-0.90), eczema (OR = 0.74, 95% CI: 0.56-0.97) and other allergies (OR = 0.65, 95% CI: 0.47-0.90). Risk was reduced for all the main histological groups. There was no significant trend of risk with age, at the onset of each condition, or the number of conditions reported. Risk reductions were strongest for asthma or hay fever with recent onset. Risk in asthmatic subjects was not related to frequency of use of antiasthmatic drugs, but was significantly reduced for use of antiallergenic medication among subjects with hay fever. The study showed an inverse association of glioma risk with allergic disease. Possible reasons for the association, as well as potential immunological aetiology, include confounding, bias and reverse causality.

Epstein-Barr virus is present in the saliva of most persistently infected individuals and is generally thought to be spread by close oral contact. However, there are now several reports of EBV in genital secretions, suggesting the possibility of sexual transmission between adults. The present study was undertaken to investigate the risk of sexual transmission of EBV. PCR analysis was used to examined the degree to which a group (n = 11) of patients with infectious mononucleosis (IM) shared the same viral isolates as their sexual partners, and compare this to the extent of isolate sharing among a different group (n = 18) of IM patients and their non-sexual contacts. There was significantly more sharing of EBV isolates among the IM/sexual-contact pairs than among the IM/non-sexual-contact pairs (P = 0.0012). Female cervical (n = 84), male urethral (n = 55), and semen (n = 30) samples from asymptomatic, unselected volunteers were analyzed for the presence of EBV DNA, revealing 7%, 5%, and 3% to be EBV positive, respectively. Fractionation of cervical and urethral samples into cellular and supernatant fluid components showed EBV to be mainly cell-associated. Quantitation of EBV in these samples gave levels of below 10 EBV genomes per microg of DNA. Overall the findings support the possibility that EBV could on occasions be transmitted sexually, however, the low levels detected in genital secretions compared to saliva suggest that this is not a major transmission route. The finding of small quantities of cell-associated virus suggests a latent infection; thus EBV is probably in the B lymphocyte rather than in the epithelial cell component of the secretions.

Tamoxifen treatment of breast cancer is associated with an increased risk of endometrial cancer, but tamoxifen-related risks of endometrial cancer are unclear in premenopausal women, in long-term users of tamoxifen, and in women for whom several years have passed since ending treatment. We conducted a case-control study in Britain to investigate these risks.

To assess pregnancy outcomes, in particular birthweight, in a large population-based cohort of women in Scotland with pre-gestational insulin-treated diabetes mellitus.

The role of antigen-specific CD3(+)CD8(+) cytotoxic T cells in the control of primary Epstein-Barr Virus (EBV) infection is well established. However, time is required for the antigen-specific immune response to develop and expand. In contrast, innate immune responses, such as natural killer (NK) cells, are considered vital early in the infection process. We analysed the scale, phenotype and function of the NK cell response during symptomatic primary EBV infection, infectious mononucleosis (IM) and showed that NK cell numbers were significantly elevated both at diagnosis of IM and in the first month following diagnosis. There were also significant changes in cell phenotype and function, an increase in the proportion of CD56(bright) cells at diagnosis, and freshly isolated cells showing an enhanced ability to kill EBV-infected cell lines. Moreover, in our cohort of IM patients higher NK cell counts were associated with significantly lower viral load in peripheral blood. Our results suggest NK cells have an important role in the control of primary EBV infection by eliminating infected B cells and augmenting the antigen-specific T cell response via release of immunomodulatory cytokines. The magnitude of the NK cell response may ultimately determine whether primary EBV infection has a clinical outcome.

Somatic mutations of BRAF have been identified in both melanoma tumors and benign nevi. Germ line mutations in BRAF have not been identified as causal in families predisposed to melanoma. However, a recent study suggested that a BRAF haplotype was associated with risk of sporadic melanoma in men. Polymorphisms or other variants in the BRAF gene may therefore act as candidate low-penetrance genes for nevus/melanoma susceptibility. We hypothesized that promoter variants would be the most likely candidates for determinants of risk. Using denaturing high-pressure liquid chromatography and sequencing, we screened peripheral blood DNA from 184 familial melanoma cases for BRAF promoter variants. We identified a promoter insertion/deletion in linkage disequilibrium with the previously described BRAF polymorphism in intron 11 (rs1639679) reported to be associated with melanoma susceptibility in males. We therefore investigated the contribution of this BRAF polymorphism to melanoma susceptibility in 581 consecutively recruited incident cases, 258 incident cases in a study of late relapse, 673 female general practitioner controls, and the 184 familial cases. We found no statistically significant difference in either genotype or allele frequencies between cases and controls overall or between male and female cases for the BRAF polymorphism in the two incident case series. Our results therefore suggest that the BRAF polymorphism is not significantly associated with melanoma and the promoter insertion/deletion linked with the polymorphism is not a causal variant. In addition, we found that there was no association between the BRAF genotype and mean total number of banal or atypical nevi in either the cases or controls.

Raised risks of several cancers have been found in patients with type II diabetes, but there are few data on cancer risk in type I diabetes. We conducted a cohort study of 28 900 UK patients with insulin-treated diabetes followed for 520 517 person-years, and compared their cancer incidence and mortality with national expectations. To analyse by diabetes type, we examined risks separately in 23 834 patients diagnosed with diabetes under the age of 30 years, who will almost all have had type I diabetes, and 5066 patients diagnosed at ages 30-49 years, who probably mainly had type II. Relative risks of cancer overall were close to unity, but ovarian cancer risk was highly significantly raised in patients with diabetes diagnosed under age 30 years (standardised incidence ratio (SIR)=2.14; 95% confidence interval (CI) 1.22-3.48; standardised mortality ratio (SMR)=2.90; 95% CI 1.45-5.19), with greatest risks for those with diabetes diagnosed at ages 10-19 years. Risks of cancer at other major sites were not substantially raised for type I patients. The excesses of obesity- and alcohol-related cancers in type II diabetes may be due to confounding rather than diabetes per se.

Mortality from acute diabetes-related events is greatly raised in young adults with type 1 diabetes. Psychosocial and socioeconomic risk factors are examined for deaths from acute events separately from deaths due to other causes.

Men with Klinefelter syndrome have one or more extra X chromosomes and have endocrine abnormalities. Case reports have led to suggestions that men with Klinefelter syndrome have elevated risks of several cancers, but published cohort studies have been relatively small. We conducted a nationwide cohort study to examine these risks.

There is public concern that use of mobile phones could increase the risk of brain tumours. If such an effect exists, acoustic neuroma would be of particular concern because of the proximity of the acoustic nerve to the handset. We conducted, to a shared protocol, six population-based case-control studies in four Nordic countries and the UK to assess the risk of acoustic neuroma in relation to mobile phone use. Data were collected by personal interview from 678 cases of acoustic neuroma and 3553 controls. The risk of acoustic neuroma in relation to regular mobile phone use in the pooled data set was not raised (odds ratio (OR) = 0.9, 95% confidence interval (CI): 0.7-1.1). There was no association of risk with duration of use, lifetime cumulative hours of use or number of calls, for phone use overall or for analogue or digital phones separately. Risk of a tumour on the same side of the head as reported phone use was raised for use for 10 years or longer (OR = 1.8, 95% CI: 1.1-3.1). The study suggests that there is no substantial risk of acoustic neuroma in the first decade after starting mobile phone use. However, an increase in risk after longer term use or after a longer lag period could not be ruled out.

About one woman in 1,000 has an extra X chromosome, but such women have no recognised characteristic somatic features and little is known about their long-term health and cancer risks. We conducted a cohort study of mortality and cancer incidence in 542 women diagnosed with X polysomy at 25 cytogenetic centres in Britain since 1959. Fifty-nine deaths occurred during follow-up to mid-2004. Mortality was significantly raised (standardised mortality ratio (SMR) = 2.5 (95% confidence interval (CI) 1.9-3.2)), with excess deaths due particularly to cardiovascular disease (SMR = 2.5 (95% CI 1.5-3.8)) and respiratory disease (SMR = 4.0 (95% CI 1.7-7.9)). Risks of cancer incidence and cancer mortality overall were not raised, but there was significantly raised mortality from non-Hodgkin's lymphoma (NHL) (SMR = 10.4 (95% CI 1.3-37.6); based on 2 cases). The data indicate that mortality in women diagnosed with X polysomy is considerably raised. The raised risk of NHL is seen also in males with more than one X chromosome, and hence although unexpected and based on small numbers, it might indicate the action of a gene on the X chromosome, possibly in the pseudoautosomal region, that escapes X-inactivation.

Klinefelter syndrome is characterized by hypogonadism and infertility, consequent on the presence of extra X chromosome(s). There is limited information about long-term mortality in this syndrome because there have been no large cohort studies.

Although the potential carcinogenic risk of radiotherapy is well known, it has become clear that there is a particularly high risk of radiation-induced breast cancer in women treated for Hodgkin's disease at young ages. Thankfully, death from breast cancer in this population is uncommon, but it is important to understand factors contributing to the risk, including treatment parameters, and to develop a logical and efficient method for medical management of those at risk. In this minireview, we examine the evidence which should inform such a management policy.

Inheritance of the T allele in exon 7 (position 18067) of the DNA repair gene XRCC3 has been reported to be associated with susceptibility to melanoma in a study from Oxford. We report a study in which an attempt was made to confirm this association in a similar population. The most potent risk factor for melanoma in the general population is a phenotype characterized by the presence of multiple melanocytic nevi: the atypical mole syndrome. Our hypothesis is that the atypical mole syndrome may be a marker of genetic susceptibility to melanoma. We have therefore investigated whether the XRCC3 polymorphism influences the nevus phenotype. The XRCC3 genotype was investigated using PCR in a general-practice-based sample of 565 women and 475 patients from a cohort enriched for the atypical mole syndrome, of whom 140 had had melanoma. Allele frequencies were the same in the healthy women, the melanoma cases from this study, and the melanoma cases reported in the Oxford study, but were different from those in the Oxford control group. We found no evidence therefore that the T allele of this XRCC3 polymorphism is indicative of susceptibility to melanoma. There was a marginal relationship with nevus phenotype, but this was no longer statistically significant in multivariate analysis. The previous association between XRCC3 and melanoma may be a result of the choice of control group and we emphasize the need for appropriate choice of controls.

To investigate mortality in South Asian patients with insulin-treated diabetes and compare it with mortality in non South Asian patients and in the general population.

The inheritance of a G allele in position 61 in the 5'UTR of the epidermal growth factor (EGF) gene has been reported to increase melanoma susceptibility, a finding we have investigated in this study. The most potent phenotypic risk factor for melanoma is the atypical mole syndrome (AMS) phenotype. Our hypothesis is that the AMS is genetically determined and that nevus genes are also low penetrance melanoma susceptibility genes. We report that the G allele frequencies were the same in 697 healthy women and 380 melanoma cases (OR 0.97, 95% CI 0.8-1.2 p=0.76). We therefore found no evidence that this polymorphism is a melanoma susceptibility gene. Furthermore, we found no evidence that the polymorphism controls the nevus phenotype (nevus number, number atypical nevi or AMS phenotype). We did find some evidence that the G allele may be associated with decreased tumor Breslow thickness (OR 0.5, 95% CI 0.3-0.9) for the A/A genotype versus A/G and G/G combined in tumors of thickness >3.5 vs less than or equal to3.5 mm and may therefore act as a predictor of survival, although this finding is not in accord with the original report. This is the second study to find no association between EGF+61 and melanoma susceptibility.

We have undertaken a comprehensive review of epidemiologic studies about the effects of radiofrequency fields (RFs) on human health in order to summarize the current state of knowledge, explain the methodologic issues that are involved, and aid in the planning of future studies. There have been a large number of occupational studies over several decades, particularly on cancer, cardiovascular disease, adverse reproductive outcome, and cataract, in relation to RE exposure. More recently, there have been studies of residential exposure, mainly from radio and television transmitters, and especially focusing on leukemia. There have also been studies of mobile telephone users, particularly on brain tumors and less often on other cancers and on symptoms. Results of these studies to date give no consistent or convincing evidence of a causal relation between RF exposure and any adverse health effect. On the other hand, the studies have too many deficiencies to rule out an association. A key concern across all studies is the quality of assessment of RF exposure. Despite the ubiquity of new technologies using RFs, little is known about population exposure from RE sources and even less about the relative importance of different sources. Other cautions are that mobile phone studies to date have been able to address only relatively short lag periods, that almost no data are available on the consequences of childhood exposure, and that published data largely concentrate on a small number of outcomes, especially brain tumor and leukemia.

The symptoms of infectious mononucleosis (IM) are thought to be caused by T cell activation and cytokine production. Surface lymphocyte activation marker (SLAM)-associated protein (SAP) regulates lymphocyte activation via signals from cell-surface CD244 (2B4) and SLAM (CD150). We followed T cell activation via this SAP/SLAM/CD244 pathway in IM and analyzed whether the results were associated with clinical severity. At diagnosis, SAP, SLAM, and CD244 were significantly up-regulated on CD4 and CD8 T cells; expression decreased during IM, but CD244 and SLAM levels remained higher on CD8 cells 40 days later. There were significantly more lymphocytes expressing CD8 and CD244/CD8 in patients with severe sore throat. The expression of CD8 alone and CD244 on CD8 cells correlated with increased virus load. We suggest that T cells expressing CD244 and SLAM are responsible for the clinical features of IM but that the control of activation is maintained by parallel increased expression of SAP.

Disease of the cardiovascular system is the main cause of long-term complications and mortality in patients with type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. Cerebrovascular mortality rates have been shown to be raised in patients with type II diabetes but have not previously been reported by age and sex in patients with type I diabetes.

Cerebral angiography using a radioactive radiological contrast medium, Thorotrast, was pioneered by Moniz in Portugal in the 1920s. Thorotrast is retained by the reticuloendothelial system, with a biological half-life of several hundred years, so that such patients suffer lifetime exposure to internal radiation. We studied mortality in Portuguese patients who were administered Thorotrast during the period 1928-1959 and in a comparison group of patients who received nonradioactive contrast agents. There were 1096 systemically exposed, 1014 unexposed, and, unique to the Portuguese study, 240 locally exposed Thorotrast patients who were successfully traced and followed up to the end of 1996. Mortality was significantly raised among systemically exposed Thorotrast patients relative to those unexposed for all causes [relative risk (RR) = 2.63], all neoplasms (RR = 6.72), liver cancer (RR = 42.4), chronic liver disease (RR = 5.12), other non-neoplastic diseases of the digestive system (RR = 4.87), neoplastic (RR = 21.9) and non-neoplastic hematological disorders (RR = 6.00), and non-neoplastic diseases of the respiratory system (RR = 4.31). Risks for most of these conditions increased significantly with time since first administration of the contrast medium and with cumulative alpha-particle radiation dose. Mortality was also significantly raised for non-neoplastic disorders of the nervous system (RR = 12.7) and ill-defined conditions (RR = 3.74), but these associations are likely to reflect the initial diagnosis, not Thorotrast exposure, because risks declined significantly with time and/or dose. There were no significant excess deaths from oropharyngeal or nasal cancers, or from any other cause, among patients exposed to Thorotrast locally for visualization of the perinasal sinuses, and no clear trend in risk with time since exposure. This study shows an association between systemic, but not local, exposure to Thorotrast and mortality from liver cancer, chronic liver disease, and neoplastic and non-neoplastic hematological disorders, with risks for these conditions remaining high for over 40 years after administration. Liver conditions, but not hematological disorders, showed a strong and consistent gradient with cumulative alpha-particle radiation dose.

This review considers in detail the descriptive and aetiological epidemiology of Hodgkin's disease and non-Hodgkin's lymphoma (NHL), with attention to histological subcategories when the literature allows. The aetiology of Hodgkin's disease remains only partially understood. There is evidence that Epstein-Barr virus (EBV) may be involved in the causation of some cases, and clinical immune deficiency is a risk factor for a few, but the evidence is not entirely consistent and other factors may also be important in causing the EBV-associated cases of Hodgkin's disease. The cause of EBV-unassociated cases remains obscure. For NHL, although it has been shown that some cases are related to immune deficiency and chronic antigenic stimulation, and especially to EBV in the context of immune deficiency, the causation of the majority of cases remains unknown. The increasing incidence of NHL, other than that related to AIDS, is also essentially unexplained. Epidemiological investigation of the aetiology of NHL and Hodgkin's disease is making steady progress, however, and there remain leads to be followed that may result in a better understanding and hence prevention.

Although ischaemic heart disease is the predominant cause of mortality in older people with diabetes, age-specific mortality rates have not been published for patients with Type 1 diabetes. The Diabetes UK cohort, essentially one of patients with Type 1 diabetes, now has sufficient follow-up to report all heart disease, and specifically ischaemic heart disease, mortality rates by age.

It has been known for more than 20 years that there is an increased risk of lymphoid neoplasia after cardiothoracic transplantation. Recent studies have demonstrated the importance of primary Epstein-Barr virus (EBV) infection and type of immunosuppressive therapy to the cause of these neoplasms, but the contribution of other factors remains equivocal.

Dense mammographic parenchymal patterns are associated with an increased risk of breast cancer. Certain features of body size have been found to be associated with breast cancer risk, but less is known about their relation to breast density. We investigated the association of birth size, childhood growth and life-course changes in body size with Wolfe grade in 1298 perimenopausal women from a British cohort of women born in 1946. The cohort benefits from repeated measures of body size in childhood and adulthood. We obtained mammograms for 90% of women who at age 53 years reported having previously had a mammogram. We found no associations with birth weight or maximum attained height. Body mass index (BMI) at age 53 years and breast size were independently and inversely associated with Wolfe grade (P-value for trend <0.001 for both). Women who reached puberty later were at a greater odds of a higher Wolfe grade than women who had an earlier puberty (odds ratio associated with a 1 year delay in menarche 1.14, 95% CI: 1.01-1.27, adjusted for BMI and breast size at mammography). A higher BMI at any age during childhood or adult life was associated with a reduction in the odds of a higher Wolfe grade, after controlling for breast size and BMI at mammography, for example, standardised odds ratio for height at age 7 was 0.72 (95% CI: 0.64, 0.81). These findings reveal the importance of taking life-course changes in body size, and not just contemporaneous measures, into account when using mammographic density as an intermediate marker for risk of breast cancer.

To investigate risk factors for Creutzfeldt-Jakob disease (CJD) in patients in the United Kingdom treated with human pituitary growth hormone (hGH).

Data regarding the effects of oral contraceptive use on women's risk of melanoma have been difficult to resolve. We undertook a pooled analysis of all case-control studies of melanoma in women completed as of July 1994 for which electronic data were available on oral contraceptive use along with other melanoma risk factors such as hair colour, sun sensitivity, family history of melanoma and sun exposure. Using the original data from each investigation (a total of 2391 cases and 3199 controls), we combined the study-specific odds ratios and standard errors to obtain a pooled estimate that incorporates inter-study heterogeneity. Overall, we observed no excess risk associated with oral contraceptive use for 1 year or longer compared to never use or use for less than 1 year (pooled odds ratio (pOR)=0.86; 95% CI=0.74-1.01), and there was no evidence of heterogeneity between studies. We found no relation between melanoma incidence and duration of oral contraceptive use, age began, year of use, years since first use or last use, or specifically current oral contraceptive use. In aggregate, our findings do not suggest a major role of oral contraceptive use on women's risk of melanoma.

Growth hormone raises serum concentrations of insulin-like growth factor IGF-I, which is mitogenic and antiapoptotic. There is evidence that raised endogenous levels of growth hormone and IGF-I might be associated with increased risk of certain solid cancers, but there have been no data on long-term risks of solid cancers after growth hormone treatment.

There is concern about the long-term health impact of ovarian stimulation treatment for infertility, in particular the effect on cancer risk. The aim of this study was to investigate the incidence of cancer in a cohort of women attending a large infertility clinic in the UK.

Breast cancer etiology in women may relate to exposures early in life as well as in adulthood, but it has been difficult to gain information on childhood variables, and evidence on their effects is very limited. Comparison of risk factor levels between affected probands and unaffected twins in twin pairs can provide a unique method to investigate risk factors that act in early life.

To determine the role of sexual contact in transmission of Epstein-Barr virus (EBV) and occurrence of infectious mononucleosis (IM), a cross-sectional study was undertaken of EBV serologic testing and histories of IM and sexual behavior among 1006 new students at Edinburgh University. Prevalence of EBV seropositivity was significantly greater among women (79.2%) than among men (67.4%; P<.001) and among those who had ever been sexually active (82.7%) than among those who had not (63.7%; P<.001). Having a greater number of sex partners was a highly significant risk factor for EBV seropositivity. Two thirds of IM cases, but only a tenth of asymptomatic primary EBV infections, were statistically attributable to sexual intercourse. The findings suggest that EBV transmission occurs during sexual intercourse or closely associated behaviors. Transmission in this way appears to account for most cases of IM but for only a minority of cases of asymptomatic EBV infection, which mainly occur at younger ages.

Epstein-Barr virus (EBV)-associated post-transplantation lymphoproliferative disease (PTLD) is a common, often fatal, complication of bone-marrow and solid-organ transplantation. Since tumour growth results from inadequate T-cell control of latent EBV, new immunotherapeutic approaches to treatment are being pioneered.

Melanocytic nevi are the most potent risk factors for melanoma yet identified. Variation in the nevus phenotype within a population is predominantly genetically determined. Genes that determine nevus expression may therefore act as low penetrance melanoma susceptibility genes. Rare germline mutations in CDKN2A predispose to melanoma and appear to be nevogenic, although the correlation between nevus phenotype and mutation status is poor. It is plausible that more common CDKN2A variants may influence both melanoma susceptibility and nevus susceptibility. Ala148Thr is a G to A missense polymorphism of CDKN2A, which is found in 4%-6% of the general population. We have investigated the role of Ala148Thr as a low penetrance melanoma or nevus susceptibility allele in two separate groups of individuals. The first was a sample of 488 adults recruited from 179 families of patients with the atypical nevus phenotype and/or a family history of melanoma, and the second was a population-based sample of 599 women. Similar prevalences of Ala148Thr (4.9% and 5.2%) were found in both samples but significant variation in the prevalence of the polymorphism was seen across geographic areas within England. There was no association between Ala148Thr status and nevus number or history of melanoma, and therefore the results did not support the hypothesis that the Ala148Thr variant is a low penetrance melanoma or nevus susceptibility allele. A significant protective role of Ala148Thr on the number of atypical nevi was observed in the family sample (mean of I atypical nevus in those with the allele and 3.5 nevi in those without, p = 0.02). After allowing for potential confounders this was not evident in the population-based sample.

If infections are involved in the aetiology of childhood leukaemia then seasonal variation in the birth or onset dates of the malignancy may be apparent. Previous studies that have examined seasonality of these dates have produced conflicting results. Using population-based data from the National Registry of Childhood Tumours we conducted a larger study than any to date of 15 835 cases of childhood leukaemia born and diagnosed in the UK between 1953-95. We found no evidence of seasonality in either month of birth or month of diagnosis overall or in any subgroups by age, sex, histology or immunophenotype. We did however find a significant (P = 0.01) February peak in month of birth for cases born before 1960 and a significant (P = 0.02) August peak in month of diagnosis for those diagnosed before 1962. Whilst these findings may be due to chance they are also consistent with changes over time in the seasonality of exposure, or immunological response, to a relevant infection. Changes in the seasonal variation in the fatality rate of a pre-leukaemic illness, such as pneumonia, could be another explanation.

To investigate the causes of the raised risk of lung cancer in patients who have had Hodgkin's disease, and in particular the relationship to treatment.

A cohort study of 1425 persons with Down's syndrome (DS), and of their parents (447 mothers, 435 fathers) and siblings (1176), was set up to investigate death rates from various causes and cancer incidence patterns. In individuals with DS the all-cause death rate was six times that of the national population (SMR = 622: 95% CI 559-693), the excess being attributable to many different causes. These included: leukaemia (SMR = 1304: 95% CI 651-2334); diabetes mellitus (SMR = 982: 95% CI 267-2515); Alzheimer's disease (SMR = 22028: 95% CI 7137-51326); epilepsy (SMR = 1727: 95% CI 744-3403); and congenital anomalies (SMR = 4987: 95% CI 4175-5955). The overall survival showed marked improvements for successive birth cohorts, particularly at young ages. For mothers and fathers of persons with DS, all-cause death rates were 20% lower than national rates and there were no significant excesses from any specific cause. For siblings, all-cause death rates were similar to national rates; the only condition with a significantly raised mortality ratio was colo-rectal cancer (SMR = 793: 95% CI 216-2031), but this may well be a chance finding.

Mortality and cancer incidence were assessed in a cohort of 1373 patients with numerical sex chromosome abnormalities diagnosed at three cytogenetics centres in Britain during 1959-90, and were compared with expectations from national rates. Four hundred patients with Turner's syndrome were followed, of whom 62 died, with a relative risk (RR) of death of 4.16 (95% confidence interval (CI) 3.22-5.39). Turner's syndrome patients had greatly raised risks of death from diseases of the nervous, cardiovascular, respiratory, digestive and genitourinary systems. One hundred and sixty three deaths occurred among 646 patients with Klinefelter's syndrome with a 47,XXY constitution, giving an RR of 1.63 (1.40-1.91). Mortality in these patients was significantly raised from diabetes and diseases of the cardiovascular, respiratory and digestive systems. There was also significantly increased mortality for patients with X polysomy (RR = 2.11 (1.43-3.02)) and Y polysomy (RR = 1.90 (1.20-2.85)), the former with significantly increased mortality from cardiovascular disease and the latter from respiratory disease. The only significantly raised risks of cancer incidence or mortality in the cohort were for lung cancer and breast cancer in patients with Klinefelter's syndrome with a 47,XXY constitution, and non-Hodgkin's lymphoma in men with more than three sex chromosomes.

Cancer incidence in the Falkland Islands, 1989-2000, was compared with rates in England and Wales, from which most Islanders originate. Colon and rectum cancer incidence was significantly raised 1989-93 but greatly reduced after 1994, when colonoscopic screening in high-risk families and sigmoidoscopic screening in the general population were introduced.

Exposures to extremely low-frequency electric and magnetic fields (EMF) emanating from the generation, transmission, and use of electricity are a ubiquitous part of modern life. Concern about potential adverse health effects was initially brought to prominence by an epidemiologic report two decades ago from Denver on childhood cancer. We reviewed the now voluminous epidemiologic literature on EMF and risks of chronic disease and conclude the following: a) The quality of epidemiologic studies on this topic has improved over time and several of the recent studies on childhood leukemia and on cancer associated with occupational exposure are close to the limit of what can realistically be achieved in terms of size of study and methodological rigor. b) Exposure assessment is a particular difficulty of EMF epidemiology, in several respects: i) The exposure is imperceptible, ubiquitous, has multiple sources, and can vary greatly over time and short distances, ii) The exposure period of relevance is before the date at which measurements can realistically be obtained and of unknown duration and induction period. iii) The appropriate exposure metric is not known and there are no biological data from which to impute it. c) In the absence of experimental evidence and given the methodological uncertainties in the epidemiologic literature, there is no chronic disease for which an etiological relation to EMF can be regarded as established. d) There has been a large body of high quality data for childhood cancer, and also for adult leukemia and brain tumor in relation to occupational exposure, Among all the outcomes evaluated in epidemiologic studies of EMF, childhood leukemia in relation to postnatal exposures above 0.4 muT is the one for which there is most evidence of an association. The relative risk has been estimated at 2.0 (95% confidence limit: 1.27-3.13) in a large pooled analysis, This is unlikely to be due to chance but, may be, in part, due to bias, This is difficult to interpret in the absence of a known mechanism or reproducible experimental support. In the large pooled analysis only 0.8% of all children were exposed above 0.4 muT. Further studies need to be designed to test specific hypotheses such as aspects of selection bias or exposure, On the basis of epidemiologic findings, evidence shows an association of amyotrophic lateral sclerosis with occupational EMF exposure although confounding is a potential explanation. Breast cancer, cardiovascular disease, and suicide and depression remain unresolved.

To assess long-term site-specific risks of second malignancy after Hodgkin's disease in relation to age at treatment and other factors.

The prognosis of Hodgkins disease (HD) has improved during the last 30 years. This study was planned to analyse long-term survival of LID patients and to compare survival rates estimated from clinical trials and population-based data. Individual data were analysed on 2,755 adult HD patients entering randomised clinical trials of the British National Lymphoma Investigation BN LI) between 1970 and 1987, and 5,064 patients with HD incident 1978-1984 recorded in the UK population-based cancer registries participating in the EUROCARE study. Relative survival of Hodgkins disease patients allowing for mortality expected from general population rates was analysed by a proportional hazards regression model including covariates. Although relative mortality decreased with longer follow-up, it was still significantly positive at 9-10 years after diagnosis in both the clinical trials and the population-based data sets. Relative mortality was worse for late stage than for early stage patients even at 10-15 years after first treatment (BNLI data). Whereas 10-year relative survival was identical in trials and population-based patients at ages under 45 years (> 69%), it was much higher in BNLI older patients than in the population-based patients. In the older age group (65-74 years) the BNLI patients had 39% relative survival whilst for the population-based patients it was only 27%, Generalisation of clinical trials results to the general population must be done with caution, especially for older patients.

Organ transplantation is associated with a greatly increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD), which is often fatal. There has been little epidemiological analysis, however, of the risk factors for LPD in transplant patients and none on whether the risks of non-EBV-associated lymphoid neoplasms are also increased.

Workers in the steel industry are exposed to various severe hazards. This study investigated risk factors for non-fatal injury occurring in the workplace and during travel to and from work in steelworkers in Brazil.

We have examined the relationship between birthweight and risk of breast cancer, taking into account growth in childhood, using data on a total of 2221 women born in 1946 and followed up to 1997. Thirty-seven breast cancers occurred during follow-up. There was evidence of greater risk of breast cancer with greater birthweight (rate ratio = 1.76 (95% CI: 0.92, 3.35) for birthweight >/= 3.5 kg vs birthweight < 3.5 kg), which was more marked at pre-menopausal ages (RR = 2.31, 95% CI: 0.93, 5.74). The relation with birthweight was not substantially confounded by any of the measured adult risk factors. A significant interaction was observed between the effects of birthweight and height at age 7 years. Relative to those born lighter than 3.5 kg, women who were heavy at birth (>/= 3.5 kg) and short or average at 7 years (< 1.22 m) had a 21% increase in breast cancer rates (RR = 1.21; 95% CI = 0.49-2.99), while women who were heavy at birth (>/= 3.5 kg) but tall at 7 years (>/= 1.22 m) had a four-fold increase (RR = 4.01; 95% CI = 1.82-8.83). These results suggest that the effect of birthweight on breast cancer risk may be modulated by childhood growth.

GH is increasingly used for treatment of children and adults. It is mitogenic, however, and there is therefore concern about its safety, especially when used to treat cancer patients who have become GH deficient after cranial radiotherapy. We followed 180 children with brain tumors attending three large hospitals in the United Kingdom and treated with GH during 1965-1996, and 891 children with brain tumors at these hospitals who received radiotherapy but not GH. Thirty-five first recurrences occurred in the GH-treated children and 434 in the untreated children. The relative risk of first recurrence in GH-treated compared with untreated patients, adjusted for potentially confounding prognostic variables, was decreased (0. 6; 95% confidence interval, 0.4-0.9) as was the relative risk of mortality (0.5; 95% confidence interval, 0.3-0.8). There was no significant trend in relative risk of recurrence with cumulative time for which GH treatment had been given or with time elapsed since this treatment started. The relative risk of mortality increased significantly with time since first GH treatment. The results, based on much larger numbers than previous studies, suggest that GH does not increase the risk of recurrence of childhood brain tumors, although the rising trend in mortality relative risks with longer follow-up indicates the need for continued surveillance.

This study investigated the influence of sociodemographic and occupational factors on the risk of 1st injury among Brazilian steelworkers.

Early life and anthropometric risk factors for testicular cancer were examined in a case-control study in England and Wales in which affected male twins were compared with their unaffected male co-twins. Questionnaire data was obtained for 60 twin pairs. Significantly raised risk of testicular cancer occurred in twins who had longer arms and legs than their co-twin. There was a significant excess of testicular cancer reported in non-twin brothers, as well as in twin brothers, of cases. Risk was also significantly raised in relation to cryptorchidism. The results on limb length suggest that factors, perhaps nutritional, affecting growth before puberty, may be causes of testicular cancer. The results on risk in brothers add to evidence of a large genetic component in aetiology of the tumour. The risk associated with cryptorchidism in the twins accords with the hypothesis that cryptorchidism is causally associated with testicular cancer because it is a cause of the malignancy, rather than because the same maternal factors experienced in utero cause both conditions.

To assess mortality in patients with diabetes incident under the age of 30 years.

To measure cause-specific mortality, by age, in patients with insulin-treated diabetes incident at a young age.

This study examined the association between numbers of benign melanocytic naevi in 7-year-old children in Oxfordshire born in 1988-9 with their mother's arm naevus count, and maternal and child pigmentation factors. We believe this is the first time that the relationship between child and maternal naevus counts has been reported. A high naevus count in the child was associated with male sex (P = 0.009), freckling (P = 0.001) and propensity of the child to burn in the sun (P = 0.05). A low naevus count was observed in red-haired children (P = 0.02). The strongest association of child's naevus count was with a high maternal arm naevus count, independent of the child's pigmentation factors (trend P < 0.0001). Maternal pigmentation factors were not associated with child's naevus count independent of the child's own pigmentation factors. Maternal arm naevus counts may be a better predictor of child naevus count than the child's own pigmentation factors and children. There has not been examination, however, of the relationship between naevus counts in children and those in their parents. We therefore conducted a study of the occurrence of naevi in children aged 7-8 years in Oxfordshire, examining, in addition to sex and pigmentation factors in the child, the relationship of maternal pigmentation factors and maternal naevus counts with naevi in their offspring.

The incidence of testicular cancer has been increasing markedly in most industrialised countries. This rise is known to have affected young adults, but it is less clear whether it has affected other age groups, particularly children. We used data from the National Cancer Registry file at the Office of National Statistics (ONS) and the National Registry of Childhood Tumours to examine trends in testicular germ-cell malignancies overall in England and Wales from 1962 to 1990 and in children from 1962 to 1995. The incidence of testicular cancer at all ages rose by 3.4% (95% CI 3.3-3.6%) per annum from 1962 to 1990. A similar rise in the incidence of germ-cell malignancies occurred during the years for which histological information was available in the ONS files, 1971-1989 (3.4%; 3.1-3.6%), to which both seminomas and non-seminomas contributed equally. The incidence of non-seminomas in adults rose in men under age 55 years and declined in older men, whereas there were increases in the incidence of seminomas in both young and older men. Cohort analysis at young ages showed a marked rise in the risk of germ-cell malignancies up to the cohort born in 1955-1959 but no further rise for those born subsequently. The rise in the incidence of these tumours in young adults was paralleled by a similar trend, although less marked, in children aged under 15 years (1.3% per annum; 0.2-2.5%). The increase in risk for children in this very large data set alongside the rise in young adults is compatible with the hypothesis that childhood and adult testicular germ-cell malignancies may have some common risk factors, presumably pre-natal.

Sun exposure is a known cause of melanoma, and there are several reasons for concern that tanning lamp use may also cause melanoma, especially because of the spectral output of the lamps,the similarity of tanning lamp use to natural sun exposure (particularly sunbathing), the reported association of melanoma with PUVA therapy, and the positive results in several case-control studies of melanoma risk and tanning lamp use. We have reviewed the epidemiologic literature relevant to the relation between tanning lamp use and melanoma and have discussed methodologic issues that should be considered in interpreting these reports and designing improved studies. Although several investigations have found a positive relation between tanning lamp use and melanoma, in some instances including dose-response or duration-response effects, the methodologic limitations preclude any firm conclusion regarding a causative relation. Meta-analysis of existing data may provide better information, but several limitations could only be overcome by new studies collecting more precise exposure data. The popularity of tanning lamp use, especially in young persons, adds urgency to the quest for elucidation of the relation between the use of these devices and melanoma risk.

Secular and cohort trends in mortality from cancer in Scotland during 1953-93, and incidence during 1960-90, were analysed using individual records from the national mortality and registration files. For certain cancer sites, the secular analyses of mortality were extended back to 1911 by use of published data. Mortality from cancer at older ages in Scotland has increased over the last 40 years. In each sex, this trend has been dominated by the effects of smoking: all-cancer rates and rates of lung cancer, now the most common fatal cancer in men and in women in Scotland, reached a peak in the cohort of men born at the turn of the century and the cohort of women born in the 1920s. For much of the period, the Scottish all-age rates of lung cancer were the highest reported in the world; they are now decreasing on a secular basis in men, but are still increasing in women. There have also been large increases at older ages in the incidence and mortality rates for cancer of the prostate in recent years. bladder cancer, nervous system cancer, non-Hodgkin's lymphoma, myeloma and leukaemia; for each there is likely to be a considerable artefactual element to the increase, with differing degrees of possibility that there may in addition be an element of real increase. Substantial decreases in mortality at all ages have occurred for stomach and colorectal cancers and substantial increases at all ages for pleural cancer and melanoma. Rates of mortality from breast cancer, the most common cancer in women in Scotland, have generally increased over the past 80 years; a temporary cessation in this upward trend occurred in the years during and after the Second World War, and recently rates have turned downward, probably at least in part because of better treatment. Mortality from ovarian cancer, the second most common reproductive-related female tumour in Scotland, has also increased at older ages. At younger ages, mortality from cancer in Scotland has decreased, especially in men, whereas incidence has not. This divergence, which has been a consequence of better treatment, has occurred especially for cancers of the testis and ovary, Hodgkin's disease and leukaemia. There have been increases at young adult ages, however, in both mortality from and incidence of oral and pharyngeal, oesophageal and laryngeal cancers in men, and melanoma and non-Hodgkin's lymphoma in each sex. Cervical cancer rates at young ages also increased, but this trend has reversed for incidence in the most recent birth cohorts. Incidence rates have also increased for testicular cancer in young adults and leukaemia in children. With the possible exceptions of non-Hodgkin's lymphoma and childhood leukaemia, the increasing rates are likely largely to reflect real rises in incidence, and they highlight the need for investigation of the causes of these cancers, and, when causes are known, for preventive action.

Using data from the Oxford Record Linkage Study (ORLS), we conducted a case-control study to estimate the sex-specific risks of inguinal hernia in siblings of children with this condition. There were 1921 male and 347 female cases born during 1970-86 who were operated on for inguinal hernia at ages 0-5 years during 1970-87, with 12,886 male and 2534 female control subjects. The relative risk of inguinal hernia was 5.8 [95% confidence interval 4.0-8.4] for brothers of male cases and 4.3 [2.1-8.7] for brothers of female cases (both relative to brothers of control subjects). The relative risk was 3.7 [1.8-7.9] for sisters of male cases and 17.8 [6.9-46.3] for sisters of female cases (both relative to sisters of control subjects). The pattern of sex-dependent risks, particularly the large risk for sisters of female cases, suggests a multifactorial threshold model for the disease. Girls have much lower rates of inguinal hernia than boys, and if these rates are low because of a low susceptibility to disease due to the absence of a sex-related risk factor, then those girls who develop disease might have a potentially large contribution to susceptibility from genetic or intrauterine risk factors unrelated to sex.

Using data from the Oxford Record Linkage Study (ORLS) we conducted a case-control study to examine pre-natal and early life risk factors for childhood and adolescent onset diabetes mellitus.

To determine mortality in patients with congenital adrenal hyperplasia (CAH) compared with that in the general population.

Using data from the Oxford Record Linkage Study (ORLS), we conducted a case-control study to examine prenatal risk factors for cryptorchidism. We identified 1449 boys born during 1970-86 for whom there was a record of an orchidopexy during 1970-87. Up to eight controls were matched to each case on year of birth and hospital or place of delivery. For each boy and his mother we extracted abstracts of maternity and general hospital records from the ORLS. Low birthweight (trend P < 0.001), low social class (trend P < 0.001), breech presentation (relative risk 1.67; 95% confidence interval [CI] 1.16, 2.41), pre-eclampsia (1.17 [1.00, 1.37]), artificial feeding (1.22 [1.04, 1.45]) and episiotomy (1.13 [1.00, 1.27]) were identified as independent risk factors for cryptorchidism. Gestational age was not independently associated with cryptorchidism after adjusting for birthweight (P = 0.33), and this observation suggested that some cryptorchid boys may have suffered from intrauterine growth retardation. Low birthweight, breech presentation and pre-eclampsia may have in common poor placental function and impaired fetal growth, which may be causes of cryptorchidism.

Cohort studies often compare the observed number of cases arising in a group under investigation with the number expected to occur on the basis of general population rates. The general population is taken to represent unexposed persons, but it is almost inevitably biased in that it comprises all types of people including exposed ones. To identify circumstances when this bias matters, the authors modeled its effect in relation to the size of the observed standardized mortality ratio (SMR) and the prevalence of exposed individuals in the general population. The authors found that bias may be a major problem, causing substantial underestimation of the true relative risk, when either the prevalence of exposure in the general population or the SMR are large. The bias can cause an apparent trend in SMRs with age when none exists. It also places a limit on the maximum size of the observed SMR, no matter how large the true relative risk. A table is provided showing the extent of bias in different circumstances. Cohort studies of people with common diseases or exposures, or that find large SMRs, when using general population expectations, need to consider the extent of bias from this source.

Risk of second primary malignancy was assessed in follow-up to June 1991 of 1039 patients first treated for Hodgkin's disease at the Royal Marsden Hospital during 1963-91. A total of 77 second malignancies occurred. There were significantly raised risks of stomach [standardized incidence ratio (SIR)=4.0], lung (SIR=3.8), bone (SIR=26.5), soft tissue (SIR=16.9) and non-melanoma skin (SIR=3.9) cancers, non-Hodgkin's lymphoma (SIR=4.6), and acute and non-lymphocytic leukaemia (SIR=31.3), with a relative risk of 3.3 for all second cancers other than non-melanoma skin cancer. Solid cancer risk was raised to a similar extent in patients treated only with radiotherapy (SIR=2.6, P<0.001), only with chemotherapy (SIR=2.1, P=0.08) and with both (SIR=3.1, P<0.001). Leukaemia risk was raised only in those receiving chemotherapy, whether alone or with radiotherapy. The relative risk for solid cancers was much greater in patients who were younger at first treatment (trend P<0.001), whereas leukaemia risk was greatest for those first treated at ages 25-44. For solid cancers (P<0.001) but not leukaemia (P=0.05) there was a strong gradient of greater relative risks at younger attained ages. The relative risk of second cancers overall was 27.5 at ages under 25 and 2.0 at ages 55 and above. Leukaemia and solid cancer risks in patients treated with chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP) were not significantly greater than those in patients treated with mustine, vincristine, procarbazine and prednisone (MOPP). Number of cycles of chemotherapy was significantly related to risk of leukaemia (P<0.001), and there was a trend in the same direction for solid cancers (P=0.07). The study adds to evidence that alkylating chemotherapy may increase the risk of solid cancers, and that ChlVPP does not provide a less carcinogenic alternative to MOPP chemotherapy. The very large relative risks found for solid cancers at young attained ages and in patients treated when young may have important implications as, in the long term, the majority of second malignancies after Hodgkin's disease are solid cancers. The risks of solid malignancies need clarification by larger collaborative epidemiological studies.

To determine the risk of testicular cancer in relation to undescended testis and its treatment based on recorded details of the maldescent, treatment, and biopsy from case notes.

To examine patterns of cause specific mortality in NHS hospital consultants according to their specialty and to assess these in the context of potential occupational exposures.

In a cohort of 21,816 Brazilian steelworkers we found mortality from motor-vehicle injury was twice that in the State population. A nested case-control study was therefore undertaken to investigate possible socio-demographic, medical and occupational risk factors for this increased risk.

To estimate the relative risk of death from work related injury in a steelworks, associated with exposure to various occupational hazards, sociodemographic factors, and medical history.

Aetiology of breast and testicular cancers may have prenatal factors, possibly exposure of the fetus to high concentrations of maternal oestrogen. Dizygotic twinning probably involves high hormone concentrations, and therefore, dizygotic twins might be at raised risk of these cancers. The aetiologies of breast and testicular cancers have genetic components, for breast cancer, especially at younger ages. Twins of these probands may, therefore, be at high risk. We investigated risk in twins of patients with breast cancer at young ages or with testicular cancer.

Mortality from cancer and other causes in male and female first-degree relatives of women with breast cancer diagnosed before age 60 has been examined in a large population-based cohort study, providing estimates of familial risks free from ascertainment or recall bias. Relatives of 3,295 patients with breast cancer diagnosed in the UK between 1954 and 1981 were identified through a register of households established in 1939. The 11,678 first-degree relatives thus identified were followed up through national records until the end of 1992. Over this period 5,421 deaths (including 1,527 cancer deaths) occurred in these relatives. Mortality from breast cancer was significantly raised in first-degree relatives (SMR 187, 248 deaths), and there was also significant excess mortality from cancers of the larynx (SMR 177, 17 deaths), endometrium (SMR 166, 29 deaths) and unspecified neoplasms (SMR 153, 70 deaths). The SMR for ovarian cancer was 130, based on 58 deaths (p = 0.06). There was no marked excess for other sites or for non-neoplastic causes of death, but there was a significant deficit in mortality from cervical cancer (SMR 63, 18 deaths). The SMR for breast cancer increased significantly with decreasing age of the relative. After allowing for age, sisters of cases had a slightly (though non-significantly) higher risk than mothers (ratio of SMRs 1.22). These results, together with penetrance estimates from linked families, suggest that approximately one woman in 800 carries BRCAI, the susceptibility gene on chromosome 17q, and that this gene causes about 1% of all breast cancers.

Mortality from cancer and other causes in first-degree relatives of women with ovarian cancer diagnosed before age 60 has been examined in a large population-based cohort study in England and Wales. Relatives of 1,188 ovarian-cancer cases diagnosed between 1954 and 1981 were identified through a register of households established in 1939. Some 4,111 first-degree relatives living in the same household and having the same surname as the index case were followed up through national records until the end of 1992. Over this period, 1,950 deaths (including 574 cancer deaths) occurred in the relatives. Mortality rates within the cohort were compared with age-, sex- and period-adjusted mortality rates for England and Wales. Mortality from ovarian cancer in first-degree relatives was significantly raised (SMR 223, 95% CI 155-310) although the excess was smaller than that found in case-control studies. The SMR increased with decreasing age of the relative, though not with decreasing age of the index case. After allowing for age, sisters of cases had higher ovarian-cancer mortality than mothers (sister:mother SMR ratio 1.89, p = 0.06). The SMR was greater in individuals having 2 first-degree relatives with ovarian cancer (4 deaths versus 0.17 expected, SMR 242). Relatives of ovarian cancer cases also had significantly increased mortality from cancers of the stomach (SMR 146, 69 deaths) and rectum (SMR 150, 33 deaths), and increased mortality from colon cancer, breast cancer and pancreatic cancer which failed to reach statistical significance. Individuals having a relative with colorectal cancer and a relative with ovarian cancer showed a high mortality from both cancers (11 colorectal-cancer deaths versus 1.23 expected, 4 ovarian-cancer deaths versus 0.66 expected.

Differences between the sexes in time trends of colorectal cancer incidence 1962-87 and mortality 1960-91 in England and Wales are examined in relation to changes in female hormonal factors. There was a trend in the sex ratio of this tumour, particularly marked for the descending colon, whereby the female excess in risk at young ages has almost disappeared but the male excess at older ages has increased. This trend started for cohorts born since the 1920s and coincided with the increase in the use of oral contraceptives and, to a lesser extent, with increases in fertility. The decline has been particularly pronounced for women at young ages born since 1935-39, coinciding with the spread of oral contraceptive use to younger age groups. These results are consistent with the hypothesis that female hormonal factors may play a role in the aetiology of colorectal cancer and with the possibility that oral contraceptive use might exert a protective effect in the descending colon.

Case-control studies of prenatal risk factors for disease in later life often ascertain cases from within a defined area, trace the birth records of those cases born within the area, and select controls from birth records within the same area. Bias can occur in these studies if the disease risk factors are related to migration from the area. The effects of this bias were examined in a study in Oxfordshire, England. Cases (n = 218) of diabetes in children and young adults born during 1965-1986 were identified from hospital discharges during 1965-1986; controls (n = 753) were selected from livebirths during 1965-1986. By 1987, 219 controls (29.1%) had migrated from Oxfordshire or died. Low maternal parity and high social class were strongly related to migration, more than the other perinatal factors studied. Migration, therefore, could lead to apparent associations of diabetes risk with parity or social class. For a general instance, the authors show how much bias is caused by different degrees of migration and of association between migration and a perinatal risk factor. Examples are given of how migration can produce apparent trends in risk as well as increased or decreased individual relative risks. If more than 25% of controls migrate, bias may be appreciable.

The atypical mole syndrome (AMS) phenotype, characterised by a large number of common naevi as well as atypical naevi, has been described in families with a genetic susceptibility to melanoma. However, the importance of this phenotype for melanoma in the general population has not been conclusively determined. This study was designed to examine the types and distribution of naevi as well as the prevalence of the AMS phenotype in melanoma patients in England compared with controls. A total of 426 cutaneous melanoma cases (61% of all incident cases) aged 16-75 years were recruited between 1989 and 1993 from the north-east Thames region of the UK and 416 controls from the same age group were recruited over the same period and from the same region. Each subject answered a questionnaire covering demographic details, sun exposure history and other risk factors and underwent a skin examination with total body naevus count performed by a dermatologist. The AMS phenotype was defined using a scoring system. Atypical naevi gave the highest relative risk for cutaneous melanoma, with an odds ratio (OR) of 28.7 (P < 0.0001) for four or more atypical naevi compared with none. Many common naevi were also an important risk factor: the OR for 100 or more naevi 2 mm or above in diameter compared with 0-4 naevi was 7.7 (P < 0.0001). Melanoma was also associated with naevi on sun-exposed sites but also with naevi on non-sun-exposed sites such as the dorsum of the feet, buttocks and anterior scalp. Sixteen per cent of the cases had the AMS phenotype compared with 2% of the controls (OR 10.4, P < 0.0001). The AMS phenotype was more common in males than females (P = 0.008). The odds ratio for the presence of the AMS phenotype was dependent on age, with an odds ratio of 16.1 (95% CI 4.6-57.5) for the presence of the AMS phenotype if aged less than 40 compared with an odds ratio of 6.9 (95% CI 2.9-16.6) if aged 40 or more. The AMS phenotype was strongly predictive of an increased risk of melanoma outside the familial context.

Injury is the leading cause of death in the male working population of Brazil. An important fraction of these deaths are work related. Very few cohort studies of steel workers, and none from developing countries, have reported on mortality from injuries. This paper analyses mortality from work and non-work related injuries among Brazilian steel workers.

Reproductive outcomes and health of offspring were investigated in 340 patients with Hodgkin's disease first treated at Mount Vernon Hospital, Middlesex, England, at ages under 40 (females) or 45 (males) during 1970-91. Information on offspring was obtained from case-notes and postal questionnaires to the patients. Eleven men and 16 women who had conceived any children after treatment were then interviewed. There was no excess of stillbirths, low birthweight or cogenital malformations, and no cancers have occurred in the 49 offspring after treatment. There was a significant excess of twins, compared with national expectations, in offspring of female patients (RR = 8.52, P = 0.025). Aggregation of series from the literature also showed an excess of twins. Chromosomes from cultures of peripheral lymphocytes from 45 children born to 25 patients (11 men and 14 women) after treatment were examined for numerical abnormalities and for structural abnormalities at the 550 or greater band level of resolution. All were normal except in one child with Down's syndrome (47, XY, +21), for whom we found the origin of the trisomy was from the parent without Hodgkin's disease. The chromosome constitution was also abnormal in one miscarriage (69, XXY; originating from the parent without Hodgkin's disease) and one termination (45, X; for with the parental origin could not be determined) after treatment. The study adds to previous questionnaire data and for the first time provides data also from chromosome analysis, that offspring of patients treated in adulthood for Hodgkin's disease are not at greatly raised risk of genotoxic or other adverse outcomes as a consequence of their parent's treatment. The numbers of offspring assessed in the literature remains small, however, and surveillance of larger numbers of subjects is needed to enable reliable treatment-specific analyses.

One thousand and sixty-three twins with cancer whose co-twin was born alive were identified among patients born since September 1939 with cancers incident in England and Wales during 1971-1984 at childhood and young adult ages. Site-specific risks of cancer were analysed in relation to birth order within the twinship and sexes of the twin pair, using adjusted national birth data to give control distributions of these variables. Risk of leukaemia was increased in first-born twins, risk of testicular cancer was increased in second-born twins with female co-twins but decreased in second-born twins with male co-twins and lung cancer risk was increased in first-born twins with same-sex co-twins. Cutaneous melanoma risk was increased in persons with opposite-sex co-twins, nervous system cancer risk was increased in females with opposite-sex co-twins and Hodgkin's disease risk was increased in persons with same-sex co-twins. For most of the findings, no previous comparable analyses are available, so interpretation of the results must be provisional until the analyses can be repeated on other data. The result for leukaemia would accord with previous suggestions that leukaemia may be of prenatal origin and may sometimes lead to intrauterine death. The Hodgkin's disease result would fit with theories of an infectious aetiology, and this view is strengthened by reanalysis of previous data on paralytic poliomyelitis in twins, which show a pattern similar to that for the Hodgkin's disease patients. Cancer risk in relation to birth order and sex of twins can give novel, objective data relating to prenatal and infectious disease aetiology of cancers.

The relationship between risk of cutaneous malignant melanoma and total body and site-specific naevus counts and other host factors was investigated in a Caucasian population aged 15-84 years in New South Wales, Australia. The study sample comprised 244 cases with melanoma diagnosed in 1989-1993, and 276 controls. The strongest relationship was with total body naevus count. Risk of melanoma was raised 12 times in those with more than 100 naevi compared with those with less than 10. There were also strong risks, with odds ratios of 5 or more, associated with having multiple atypical naevi, multiple large naevi, high naevus counts in sun-exposed or sun-protected areas and being unable to tan on repeated sun exposure. The effect of inability to tan was stronger at younger than older ages. Lesser risks, with odds ratios of 2-3, were associated with being prone to burn on sun exposure, having many freckles as a child and having red hair. The site distribution of naevi in males compared with females resembled the distribution of melanoma by sex. Risk of melanoma of the back was significantly more closely related to back naevus count than naevus count for the remainder of the body. For other anatomical sites, naevus count was non-significantly more closely related to naevus counts at that site than counts over the remainder of the body. Naevus count declined with age in both cases and controls. In those aged under 40, having 100 or more naevi was associated with an aetiological fraction (AF) of 41%. In those aged 60 and over, however, the AF associated with this number of naevi was only 5%.

To determine the risk of maternal mortality in immigrants to England and Wales.

Diabetes is one of the most common chronic diseases in Western populations. There have been few large published cohort studies of people with diabetes that have had more than 10 years of follow-up, and none other than the present one are in the UK. Such studies are important to understand the long-term fatal consequences of diabetes and their variation over time and between countries.

Mortality from cancer and other causes in male and female first-degree relatives of women with breast cancer diagnosed before age 60 has been examined in a large population-based cohort study, providing estimates of familial risks free from ascertainment or recall bias. Relatives of 3,295 patients with breast cancer diagnosed in the UK between 1954 and 1981 were identified through a register of households established in 1939. The 11,678 first-degree relatives thus identified were followed up through national records until the end of 1992. Over this period 5,421 deaths(including 1,527 cancer deaths) occurred in these relatives. Mortality from breast cancer was. significantly raised in first-degree relatives (SMR 187, 248 deaths), and there was also significant excess mortality from cancers of the larynx (SMR 177, 17 deaths), endometrium (SMR 166, 29 deaths) and unspecified neoplasms (SMR 153, 70 deaths). The SMR for ovarian cancer was 130, based on 58 deaths (P = 0.06). There was no marked excess for other sites or for non-neoplastic causes of death, but there was a significant deficit in mortality from cervical cancer (SMR 63, 18 deaths). The SMR for breast cancer increased significantly with decreasing age of the relative. After allowing for age, sisters of cases had a slightly (though non-significantly) higher risk than mothers (ratio of SMRs 1.22). These results, together with penetrance estimates from linked families, suggest that approximately one woman in 800 carries BRCA1, the susceptibility gene on chromosome 17q, and that this gene causes about 1% of all breast cancers. (C) 1996 Wiley-Liss, Inc.

Mortality from cancer and other causes in first-degree relatives of women with ovarian cancer diagnosed before age 60 has been examined in a large population-based cohort study in England and Wales. Relatives of 1,188 ovarian-cancer cases diagnosed between 1954 and 1981 were identified through a register of households established in 1939. Some 4,111 first-degree relatives living in the same household and having the same surname as the index case were followed up through national records until the end of 1992. Over this period, 1,950 deaths (including 574 cancer deaths) occurred in the relatives. Mortality rates within the cohort were compared with age-, sex- and period-adjusted mortality rates for England and Wales. Mortality from ovarian cancer in first-degree relatives was significantly raised (SMR 223, 95% CI 155-310) although the excess was smaller than that found in case-control studies. The SMR increased with decreasing age of the relative, though not with decreasing age of the index case. After allowing for age, sisters of cases had higher ovarian-cancer mortality than mothers (sister:mother SMR ratio 1.89, P = 0.06). The SMR was greater in individuals having 2 first-degree relatives with ovarian cancer (4 deaths verses 0.17 expected, SMR 242). Relatives of ovarian cancer cases also had significantly increased mortality from cancers of the stomach (SMR 146. 69 deaths) and rectum (SMR 150, 33 deaths), and increased mortality from colon cancer, breast cancer and pancreatic cancer which failed to reach statistical significance. Individuals having a relative with colorectal cancer and a relative with ovarian cancer showed a high mortality from both cancers (11 colorectal-cancer deaths versus 1.23 expected, 4 ovarian-cancer deaths verses 0.66 expected). (C) 1996 Wiley-Liss, Inc.

Risk of cancer mortality from 1973 to 1985 in persons born in the Indian subcontinent who migrated to England and Wales was analysed by ethnicity, and compared with cancer mortality in the England and Wales native population, using data from England and Wales death certificates. There were substantial highly significant raised risks in Indian ethnic migrants for cancers of the mouth and pharynx, gall bladder, and liver in each sex, larynx and thyroid in males, and oesophagus in females. There were also substantial raised risks in these migrants of each sex for non-Hodgkin's lymphoma and myeloma. For the mouth and pharynx, and liver in each sex, and gall bladder in females, there were also raised risks of lesser magnitude in British ethnic migrants. For colon and rectal cancer and cutaneous melanoma in each sex, ovarian cancer in women and bladder cancer in men, there were appreciable significantly reduced risks in the Indian ethnic migrants not shared by those of British ethnicity. Appreciable raised risks in British ethnic migrants not shared by those of Indian ethnicity occurred for nasopharyngeal cancer in males, soft tissue malignancy in both sexes and non-melanoma skin cancer in males. In migrants of both ethnicities there were appreciable significantly raised risks in each sex for leukaemia and decreased risks in each sex for gastric cancer, for lung cancer except in females of British ethnicity and in males for testicular cancer. The results suggest the need for public health measures to combat the high risks of oral and pharyngeal cancers and liver cancer in the Indian ethnic immigrant population of England and Wales, by prevention of betel quid chewing and hepatitis transmission respectively. The data also imply that early exposures or early acquired behaviours in India, or exposures during migration, may increase the risk of leukaemia and reduce the risks of gastric and testicular cancers in the migrants irrespective of their ethnicity. Aetiological studies would be worthwhile to investigate the reasons for the sizeable decreased risk of colon and rectal cancer and increased risk of gall bladder cancer in each sex and the increased risk of thyroid and laryngeal cancer in males and oesophageal cancer in females of Indian ethnicity but not of British ethnicity who have migrated from the Indian subcontinent.

The effect of changes in recording and coding of cause of death on trends in cancer mortality in England and Wales in persons aged 45 and over during 1970-1990 is reviewed. During this period, all-cancer mortality rates increased only at ages over 75 in males and over 55 in females. Rises in cancer mortality were largely due to increases in cancer of lung, prostate and unspecified site in men, and of lung, breast and unspecified site in women. Death coding and certification artefacts were much larger in older persons. In those aged 75-84, a change in the position of recording cancer on the death certificate could potentially account for 46% of the recorded increase in prostate-cancer mortality and 28% of the increase in breast-cancer mortality. The decrease in recorded mortality from ill-defined terminal events was far greater than the increase in cancer mortality in this age group. The rise in all-cancer mortality in the elderly was partly due to an increase in lung-cancer mortality, and data artefacts explained a large proportion of the increase in the other common specified cancers in those aged 75-84. The use of routine mortality statistics to chart progress against cancer lacks validity at older ages because of imprecision in certification of cause of death.

Risks of cancer incidence in people born in England and Wales and New Zealand (non-Maoris) living in their home countries, and after migration between the two countries, were analysed using data from their national cancer registries. Since these populations are of similar genetic origin, any real differences in cancer incidence between them are likely to reflect the action of environmental or behavioural risk factors. The greatest differences in risk between the countries were for cutaneous melanoma and lip cancer. In each sex, relative risks of these malignancies were 4 or greater for the New Zealand-born in New Zealand compared with English and Welsh natives in their home country, and risks for migrants in each direction were generally intermediate between those born in the home country in the two countries. Sizeable significantly raised risks in the New Zealand-born in New Zealand compared with English and Welsh natives in England and Wales also occurred for cancers of the mouth, small intestine, colon, thymus, eye and thyroid, and non-Hodgkin's lymphoma in each sex, and for cancer of the prostate. For all of these sites except mouth, small intestine and colon there were also risks around or above New Zealand-born levels for English and Welsh migrants to New Zealand; for colon cancer these migrants had risks close to those in England and Wales. New Zealand migrants to England and Wales had risks of cancers of the colon and prostate that were similar to or above New Zealand levels. Risks of cancers of the stomach, lung, pleura and bladder, and Hodgkin's disease in each sex, and cancers of the cervix, ovary and scrotum and penis, were substantially and significantly lower in the New Zealand-born living in New Zealand than in English and Welsh natives in England and Wales. In English and Welsh migrants to New Zealand risks of bladder cancer in each sex, and of scrotal and penile and pleural cancer in males, approximated to England and Wales risks; cervical cancer risk approximated to the New Zealand risk; and stomach, lung and ovarian cancers showed intermediate risks. Migrants from New Zealand to England and Wales did not gain the lung cancer or clearly the stomach cancer risk of their host country, but did have bladder cancer risks approximating to those in England and Wales.(ABSTRACT TRUNCATED AT 400 WORDS)

Using individual subject data from 10 case-control studies, comprising over 3000 cases and almost 4000 controls, we have estimated the relative risk of melanoma associated with aspects of complexion, namely, hair, eye and skin colour and freckling in adulthood, and have examined the relationships between these factors and naevus count in terms of melanoma risk. Compared with individuals with black or dark brown hair, the relative risks for developing melanoma in those with light brown, blonde and red hair were 1.49 (95% CI 1.31, 1.70), 1.84 (95% CI 1.54, 2.21) and 2.38 (95% CI 1.90, 2.97), respectively. Individuals with blue eyes had a risk 1.55 (95% CI 1.35, 1.78) times that for those with brown eyes, or 1.15 (95% CI 0.94, 1.40) after adjusting for hair colour and freckling in adulthood. The relative risks associated with hair and eye colour were independent of those for naevus count and skin colour. Light skin colour and high freckle density were also highly significant risk factors, independent of each other and of naevus count and hair and eye colour. The risks associated with these factors, while individually modest, are largely independent, and thus pigmentation characteristics and freckling tendency should be useful in identifying high risk groups to be targeted for prevention.

In a combined analysis of 2952 melanoma patients and 3618 controls from 8 case-control studies in white populations the risk of cutaneous melanoma was 2.24-fold higher (95% CI, 1.76-2.86) in subjects who reported at least one affected first-degree relative than in subjects who did not. There was no evidence for heterogeneity in the relative risk between the studies, which were from a wide range of latitudes and hence degrees of sun exposure. The effect of family history on melanoma risk was independent of age, naevus count, hair and eye colour, and freckling. There was no evidence for a relationship between family history and primary site of melanoma but there was some suggestion that the familial patients were more likely to have superficial spreading melanoma or lentigo maligna melanoma than acral lentiginous melanoma or nodular melanoma.

Reproductive-related factors play a major role in the aetiology of cancers of the breast, ovary and endometrium. Pregnancy history influences the risk of each of these cancers, and oral contraceptive use modifies the risks of ovarian and endometrial cancers, although its effect on breast cancer risk is less certain. We analysed recent time trends in the incidence and mortality of these cancers in England and Wales and assessed whether they can be explained by changes in fertility and oral contraceptive use. During 1962-87, there were significant increases in the overall incidence of breast cancer (0.95% increase per annum) and ovarian cancer (0.76% per annum) but little increase in endometrial cancer (0.13% per annum). At young ages incidence of each of the cancers has declined in recent years, whereas at older ages there have been substantial increases. Mortality data show similar time trends. In analyses by birth cohort, incidence of each of the cancers increased steeply for successive cohorts born before the turn of the century, and more slowly for cohorts thereafter, reaching a maximum for those born in the 1920s, and decreased for those born subsequently. The increases in incidence for women born before the turn of the century paralleled marked declines in their fertility. The fall in risk for women born after the 1920s was not accompanied by significant increases in their fertility, but coincided with the introduction and increase in use of oral contraceptives. For ovarian and endometrial cancers this accords with strong evidence from person-based studies of the protective effect of oral contraceptives. For breast cancer, the reasons for the recent decline are not clear. It would accord with recent suggestions of a long-term protective effect of oral contraceptives, on which further studies are needed. It is also possible, however, that changes in other risk factors such as dietary fat intake and menarcheal age might have contributed to the recent declines in the risk of these cancers.

Risks of 2nd primary cancer were assessed in all patients with cutaneous melanoma (12,460) and all patients with ocular melanoma (2,018) incident in Denmark from 1943 to 1989 and followed for totals of 88,667 person-years and 16,045 person-years, respectively. After cutaneous melanoma, 972 2nd cancers occurred. The risk of non-melanoma skin cancer was significantly raised in each sex. Risk of all non-skin cancers was not raised for all ages but was significantly increased for patients with the primary melanoma incident at ages under 50 years (standardised incidence ratio [SIR], i.e., ratio of observed to expected cancer incidence, multiplied by 100 = 117; 95% confidence interval [CI] 101-134). There were significantly increased risks of chronic lymphocytic leukaemia in males and both sexes combined, brain and nervous system cancers in females and both sexes combined and oropharyngeal cancer in both sexes combined. Risk of pancreatic cancer was not raised, suggesting that cutaneous melanoma patients generally do not share the diathesis for this malignancy which has been observed in certain families with atypical naevi and melanoma. There was no relation of 2nd primary cancer risks to duration since the first primary and no indication of any appreciable treatment-related risk. After ocular melanoma, 216 2nd cancers occurred. There was a significantly increased risk of 2nd cancer overall in males but not females and a significantly increased risk of liver cancer in each sex. Risk of non-melanoma skin cancer (NMSC) was not raised, which suggests that the aetiology of ocular melanoma is not mainly dependent on UV exposure, at least of the type causing NMSC.

Giant congenital nevi are associated with a greatly increased risk of melanoma, but this has not been quantified. Smaller congenital nevi are believed by some authors to be associated with increased risk, but this is uncertain and needs to be clarified.

To investigate the possibility of a pre-invasive phase of adult germ cell tumours being detectable in childhood.

Relatively little is known about the epidemiology of carcinoid tumours in contrast to the extensive information available on their biochemical effects and natural history. Accordingly, we have used cancer registrations in England from 1979 to 1987, and in Scotland from 1980 to 1989, to estimate the incidence of carcinoid tumours in Britain. Age-standardised incidence rates for England, based on 3,382 registrations, were 0.71 (0.68-0.75) for men and 0.87 (0.83-0.91) for women, per 100,000 per year. The equivalent rates for Scotland, based on 639 registrations, were 1.17 (0.91-1.44) for men and 1.36 (1.09-1.63) for women. There was a consistent female excess of carcinoid tumours in the reproductive years, which was reversed after the age of 50. The female excess was most striking for gastrointestinal carcinoid tumours in women aged 15-19 years (F:M ratio = 2.14). The sex differences are probably due in part to incidental diagnosis of carcinoid tumours during abdominal procedures, which are more common in women than men at ages 15-49 years. However, there is some evidence to suggest a true sex difference in incidence, particularly the fact that the sex ratio for thoracic tumours varies with age in a similar way to that for gastrointestinal tumours. Hormonal factors may, therefore, be important in the aetiology of carcinoid tumours.

Lung cancer mortality in a cohort of 4320 miners first employed during 1948-1959 at the Jáchymov and Horní Slavkov uranium mines in West Bohemia and followed until 1 January 1991 has been studied to gain a greater understanding of the consequences of exposure to radon and its progeny. Among men whose exposure rates never exceeded 10 working levels, excess relative risks per unit exposure were greater in younger men, and exposures received in the periods 15-24, 25-34 and 35+ years previously were found to have 47, 24 and 0% of the effect of exposures 5-14 years previously. Within this low-exposure-rate group excess relative risk increased linearly with time-weighted cumulative exposure and did not depend on exposure rate or duration of exposure. For men who spent less than 20% of their employment at the Jáchymov mine the excess relative risk per working level month was 1.36% (95% confidence interval 0.52-3.54) in the baseline category (age group 55+ and exposure received 5-14 years previously). For men who spent more than 20% of their employment at Jáchymov, the corresponding excess relative risk per working level month was higher by a factor of 1.80 (95% confidence interval 1.27-2.97). The difference may be due to the fact that men who spent more than 20% of their employment at Jáchymov were exposed to the much higher levels of arsenic in the dust at the Jáchymov mine than at other mines. When men with exposure rates above 10 working levels were included in the analysis, patterns of risk were complex and depended on both exposure rate and duration of exposure in addition to the factors mentioned above. If these findings are confirmed elsewhere, calculation of risk estimates for extrapolation to modern occupational or environmental exposures should be based on miners with exposure rates below about 10 working levels. Further investigation is desirable of the influence of dusts containing arsenic on lung cancer risk in miners exposed to radon.

A cohort of 4320 uranium miners in West Bohemia who started work at the mines during 1948 to 1959 and worked there for at least four years were followed up to the end of 1990 to determine cause specific mortality risks in relation to exposures in the mines. The miners had experienced high radon exposures, on average 219 working level months during their uranium mining careers, for which detailed measurements were available. They had also been exposed to high arsenic levels in one of the two major mines, and to dust. New follow up methods, not previously used for occupational cohorts in Czechoslovakia, were utilised. By the end of follow up 2415 (56%) of the cohort were known to have died. Overall mortality was significantly raised compared with that in the general population (relative risk (RR) = 1.56, 95% confidence interval (95% CI) 1.50-1.63), with significantly raised risks of lung cancer (RR = 5.08, 95% CI 4.71-5.47), accidents (RR = 1.59, 95% CI 1.34-1.87), homicide (RR = 5.57, 95% CI 2.66-10.21), mental disorders (RR = 5.18, 95% CI 2.83-8.70), cirrhosis (RR = 1.51, 95% CI 1.16-1.94), and non-rheumatic circulatory diseases (RR = 1.16, 95% CI 1.08-1.25). The relative risk of lung cancer was greatest four to 14 years after entry to the mines. Relative risks for homicide and accidents were raised up to 25 years from entry but not after this. Substantial significantly raised risks at 15 to 24 years after entry occurred for cirrhosis, non-rheumatic circulatory diseases,a nd pneumonia and other respiratory infections. Sizeable significantly raised risks at 25 and more years after entry, but not earlier, were present for mental disorders, tuberculosis, and non-malignant non-infectious respiratory conditions. No specific causes showed risks significantly related to age at entry to mining. Risk of lung cancer was significantly positively related to radon exposure, estimated arsenic exposure, and duration of work in the mines, but no other cause was significantly positively related to these variables. The raised risk of lung cancer in uranium miners, which is well established, is related aetiologically to radon exposure, and in the present cohort it may also in part have been due to exposure to arsenic. The raised risks of accidents, tuberculosis, and non-infectious respiratory diseases have also been seen in other uranium mining cohorts, and are likely to reflect the dangerous and dusty working conditions and the confined spaces in which work occurred. The cirrhosis and homicide deaths probably related to the lifestyle associated with mining. The raised risk of circulatory diseases does not seem to be related to radon or arsenic exposure; its causes are unclear. The use of multiple follow up methods was found to be mortality in the cohort.

One hundred and fifty-two patients in whom a diagnosis of dermatitis herpetiformis was made at St John's Hospital for Diseases of the Skin, London, during 1950-85, were followed from the date of diagnosis to the end of 1989 for mortality, and from 1971, or the date of diagnosis if later, to 1986 for cancer incidence. Thirty-eight deaths occurred under the age of 85, slightly fewer than expected on the basis of national general population rates [standardized mortality ratio (SMR) = 87; 95% confidence interval (CI) 61-119]. All-cause mortality was somewhat lower in patients who had followed a gluten-free diet (SMR = 51; 17-120) than in those who had not (SMR = 97; 66-136), but the difference in SMRs was not significant (P = 0.3). Cancer mortality was non-significantly below expectations from national rates (SMR = 72; 31-142), but cancer incidence was significantly increased [standardized registration ratio (SRR) = 394; 180-749]. No particular cancer site accounted for the cancer incidence excess. One death occurred from cancer of the small intestine (SMR = 4953, P = 0.04), and one lymphoma was incident (SRR = 1555, P = 0.12). Increased risks of these malignancies have previously been found to be associated with coeliac disease (which is present in many patients with dermatitis herpetiformis), and with dermatitis herpetiformis, respectively. Mortality from ischaemic heart disease (IHD) was significantly below national rates (SMR = 37; 95% CI 12-86), and was similar in patients who had followed a gluten-free diet and those who had not.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent observations have suggested that radon in the ambient air may cause cancers at sites other than the lung, but the evidence is indirect. We have studied site-specific cancer mortality in 4320 uranium miners in West Bohemia who have been followed-up for an average of 25 years, and in whom a four-fold radon-related excess of lung cancer has already been established. For all cancers other than lung cancer the number of deaths observed was slightly greater than that expected from national rates, but the increase was not significant statistically (ratio of observed to expected deaths [O/E] = 1.11, 95% confidence interval [CI] = 0.98-1.24) and mortality did not increase with duration of employment underground or with cumulative exposure to radon. Non-lung cancer mortality was significantly raised among men who started mining work aged under 25 but the increase was not related to cumulative radon exposure. When twenty-eight individual sites and types of cancer were examined, significantly increased risks were found for cancers of the liver (O/E = 1.67) and gallbladder and extrahepatic bile ducts (O/E = 2.26). For liver cancer, mortality did not increase with duration of employment underground or with cumulative radon exposure. For cancer of the gallbladder and extrahepatic bile ducts, mortality did not increase with duration of employment, but increased with cumulative exposure to radon. Mortality from multiple myeloma, although not significantly increased overall (O/E = 1.08), increased with cumulative exposure to radon. Mortality from leukaemia was not increased overall (O/E = 0.91) and was not related to cumulative radon exposure, but did increase with increasing duration of employment in the mines. There is no evidence in these miners that a radon-rich atmosphere increases the risk of any cancer other than lung cancer. Possible exceptions are cancer of the gallbladder and extrahepatic bile ducts and multiple myeloma but further study is needed before it can be concluded that the associations found are causal.

The risks of second primary cancer were analysed in 2846 patients with Hodgkin's disease treated within the British National Lymphoma Investigation during 1970-87. The relative risk (RR) of leukaemia was significantly greater in women (RR = 30.1; 95% confidence limits (CL) 13.0-59.5) than in men (RR = 10.9; 95% CL 4.7-21.5), and showed a significant trend of greater risk with younger age at first treatment (P < 0.001). The relative risk of solid cancers was similar between the sexes, but again significantly greater at young than at older ages of first treatment (P < 0.01). Non-Hodgkin's lymphoma relative risks, although not related to sex or age, were significantly related to histology of the original Hodgkin's disease, and were greatest after lymphocyte predominant Hodgkin's disease (RR = 55.6; 95% CL 18.0-129.7). The relative risk of second cancers did not vary significantly according to whether or not splenectomy had been performed. Leukaemia risk was non-significantly greater after splenectomy than with no splenectomy, which accorded with previous evidence of a modest increased risk associated with this operation. If the greater relative risk of solid second cancers after treatment at young than at older ages persists with longer follow-up, the incidence rates of these second primaries in patients treated young for Hodgkin's disease will become very substantial as they age. This emphasises the need to maintain long-term follow-up surveillance of young Hodgkin's disease patients apparently cured of their disease, and to continue to develop new less carcinogenic treatment regimens.

A cohort of 412 patients first attending a cystic fibrosis (CF) clinic between 1961 and 1989 were followed up to 30 June 1989. The number of malignancies observed in the cohort was compared with the number expected based on the age, sex and calendar-year-specific cancer registration rates for England and Wales. Four CF patients were diagnosed as having malignancies before 30 June 1989. The tumours were: adenocarcinoma of the terminal ileum; adenocarcinoma of the pancreas, testicular teratoma, and B-cell lymphoma. This compares with 0.89 malignancies expected on the basis of rates in England and Wales (Standardised Registration Ratio = 452; 95% confidence interval 122-1150, P = 0.03). The single case of adenocarcinoma of the terminal ileum contrasts with less than 0.001 expected (P = 0.003) and that of the pancreas with 0.007 expected (P = 0.01). A further adenocarcinoma of the pancreas was diagnosed 2 years after the end of the study period. The two cases of pancreatic cancer compare with 0.008 expected (P = 0.0001) during the period to mid 1991. On the basis of the present findings and previous case reports in the literature adenocarcinoma of the pancreas and adenocarcinoma of the terminal ileum may be associated with cystic fibrosis.

There are marked variations in the risk of hormone-dependent cancers between males and females, and these are likely to reflect sex differences in endogenous hormone profiles. The authors examined sex differences in the risk of hormone-dependent cancers of sex-shared sites by using data from the England and Wales national cancer registry for 1962-1984. Both breast and thyroid cancers showed marked excesses in risk for women, but the female: male ratio peaked around menopause for breast cancer and a puberty for thyroid cancer, suggesting that although female sex hormones may influence the risk of these two cancers, the mechanisms involved are probably different. In the descending colon, the risk of cancer was greater in females than in males at ages under 60 years, but greatest in males at ages above this, whereas in the ascending colon there were no age-specific differences in risk between the sexes. This is consistent with the hypothesis that female reproductive events may decrease a woman's risk of cancer in the descending but not in the ascending colon. Sex differences in bone cancer risk at puberty, particularly for osteosarcomas and Ewing's sarcomas, paralleled known sex differences in skeletal growth; there was a peak in age-specific rates earlier and lower in girls than in boys. Rhabdomyosarcoma, a soft tissue cancer, also showed a rise in risk at puberty with age differences between boys and girls that correlated with sex differences in muscle growth patterns; this suggests that its etiology may be hormonally related as well.

Records of 2,145 cases of Hodgkin's disease in England and Wales treated by the British National Lymphoma Investigation during 1970-84 were sought in the national and regional cancer registers. One thousand eight hundred and eight-six (88%) were recorded in the national register, either as Hodgkin's disease (86%) or as other or unspecified lymphoma (2%) and 2 (0.1%) were recorded as other cancers. A further 69 (3%) cases were registered by regional cancer registries but had not reached the national register. Adjusting for the distribution of the study cases by region of incidence, we estimate completeness of registration of cases of Hodgkin's disease in the national register at 89.7%, and in the regional registers overall at 92.9%. Completeness did not vary appreciably by age or sex or calendar period. There was however, substantial variation in completeness between regional registries. Estimates were made for all regions except North Western; the lowest estimated completeness were under 90% in Wessex, and the Thames registry regions, and the greatest were 95% or more in Northern, Trent, East Anglia, Oxford, South Western, West Midlands and Mersey. Because these results are confined to one malignancy treated by a particular collaborative network of physicians (although a large and widespread one), and because the patients are restricted to those seen in hospitals, caution must be exercised in extrapolation of the findings to cancer registration generally, but other studies and sources of information lead to similar conclusions about completeness of cancer registration nationally and regionally.

Thyroid cancer incidence has been increasing in many countries, whereas mortality has been falling due to better survival. Radiation is the best-established risk factor and there has been concern that recent rises in incidence might be related to fallout radiation from atmospheric nuclear weapon tests. We examined thyroid cancer time trends and geographical distribution in England and Wales and possible interpretations of these. During 1962-84, there were significant increases in incidence (P < 0.001) in each sex at ages under 45. Cohort analysis by single year of birth showed an overall increase in incidence risks in women aged 0-44 born since 1920, with a sudden rise in risk for the birth years 1952-55 followed by a lower risk for the more recent cohorts. In men, there was an overall increase in risk at ages 0-44 in successive birth cohorts, but the pattern was irregular. In each sex, the risk in persons aged 45 and over decreased slightly in successive generations. Geographically, highest incidence risks were in countries in North and Mid Wales, in which the risk was almost twice that in the rest of the country. This pattern was present only at ages 45 and over and was most clear in rural areas. The peak of thyroid cancer risk in women born in 1952-55 is consistent with a carcinogenic effect of fallout radiation, since these women were children in the late 1950s and early 1960s when fallout radiation was greatest in England and Wales. The focus of high thyroid cancer risks in Wales was in areas with high levels of fallout radiation. However, thyroid cancer risks in Wales were not high for more recent cohorts (the ones who were exposed to fallout early in life), and a focus on high risk of benign thyroid diseases was present in Wales well before nuclear weapons existed. The distributions of these benign thyroid diseases, or of factors causing them, seem more likely than fallout to explain the high risk areas for thyroid cancer in the country.

To analyse the risk of second primary cancers during long term follow up of patients with Hodgkin's disease.

Cancer mortality during 1970-85 of immigrants from East and West Africa and the Caribbean to England and Wales is described. Overall cancer mortality was raised in West African males (RR 1.38, 95% CI 1.25-1.54), and non-significantly raised in West African females (RR 1.14, 0.96-1.37) compared to mortality in the England and Wales-born population. Much of the increased risk was due to very high rates of liver cancer in males (RR 31.6, 23.8-41.9), but rates were also raised for a wide range of other cancers in each sex. Only lung and brain cancer had significantly decreased mortality. In East Africans, overall cancer mortality was low in males (RR 0.63, 0.56-0.70), and in females (RR 0.80, 0.72-0.89). Mortality was significantly low for cancers of the stomach, pancreas and testis, and Hodgkin's disease in males, for cervical cancer in females, and for lung cancer and melanoma in both sexes. Cancer sites with significantly raised mortality included oropharyngeal cancer, leukaemia, and multiple myeloma in both sexes. In Caribbean immigrants overall cancer rates were significantly low in males (RR 0.71, 0.68-0.74) and in females (RR 0.76, 0.73-0.80). Mortality was significantly low for many cancers including colorectal, lung, testis and brain cancers. Mortality was significantly raised only for cancer of the prostate in males, of the placenta in females, and of the liver, non-Hodgkin's lymphoma and multiple myeloma in both sexes. Overall, mortality was high from prostatic cancer and liver cancer, and was low from brain cancer, in predominantly ethnic African immigrant groups. Both East and West African immigrants had raised rates of leukaemia. All of the migrant groups had high rates of multiple myeloma and low rates of testicular, ovarian and lung cancer. Genetic and environmental factors that may contribute to these patterns are discussed.

The epidemiological features of Kaposi's Sarcoma (KS) incidence in England and Wales in the period 1971-1980 are reviewed. The epidemiology of KS in England and Wales in this period is distinct from that associated with the AIDS epidemic. The incidence was probably very low compared to other Western countries, there was little male excess, and no indication, based on marital status data, of a raised incidence in male homosexuals. Half the cases registered were in people born outside the UK. The region of birth distribution in these migrants reflected the known pre-AIDS geographic distribution of KS and also pointed to high risks in those from Middle Eastern countries and the Caribbean. The very low incidence rates of KS in natives of England and Wales suggests that the background prevalence of the causative agent for KS was low in England and Wales prior to the AIDS epidemic.

For the last 20 years the National Health Service Central Register (NHSCR) has been used as the principal source of follow-up for mortality, and often for cancer incidence, in many cohort and clinical follow-up studies in England and Wales. Completeness of notification of childhood cancer registrations and deaths from the NHSCR was investigated by comparison between cancers and deaths notified to the Childhood Cancer Research Group (CCRG) from this source and notifications received directly from regional cancer registries and the national death registry. Six thousand, seven hundred and seventy-six (91.8%) of 7,379 cancers incident 1971-84, and 588 (95.8%) of 614 deaths occurring 1953-88, were successfully notified. Failures in cancer notification occurred mainly between the regional cancer registries and the National Cancer Register (3.3%), and between the National Cancer Register and the NHSCR (3.0%). An additional 1.9% of cancer notifications failed between the NHSCR and the CCRG. Incompleteness of registration of childhood cancers by regional cancer registries was estimated to be 4.7%. A total of 12.5% of incident childhood cancers were not notified by NHSCR. Incompleteness of notification may be greater for adults, for whom registration and record linkage may be more difficult. Failures in death notifications occurred mostly because deaths entered on the NHSCR were not notified to the CCRG (3.3%). This incompleteness of notification needs to be taken into account in the interpretation of published studies and in the analysis of studies using NHSCR flagging. It also implies similar incompleteness in published national cancer survival data, which use the same system of flagging. Nevertheless it is a notable achievement that NHSCR has successfully monitored such a high proportion of a population of 50 million people, by entirely clerical procedures, for 40 years.

Trends in diabetes-related mortality in England and Wales between 1975-6 and 1985-6, and regional and ethnic differences in diabetes-related mortality in 1985-6, have been examined. Data from death certificates mentioning diabetes in 1975-6 were compared with those for 1985-6 for different age groups. Data for 1985-6 were also analysed for different regions of England and Wales, and for country of birth. Between 1975-6 and 1985-6, the age-standardized rate of mentioning diabetes rose by 2.7% (95% confidence interval 1.4%, 4.1%) in men of all ages, and fell by 11.7% (10.6, 12.8) in women of all ages. By contrast, the rate of mentioning diabetes in those below 45 years fell by 30.7% (23.0, 37.7) in men and by 26.7% (16.5, 35.6) in women. Deaths in which the underlying cause was ischaemic heart disease (IHD), and where diabetes was also mentioned on the death certificate, rose by 14.4% (11.5, 16.8) in men and did not change significantly in women of all ages, but fell by 18.4% (-35.1, +2.6) in men, and 23.5% (-49.1, +15.2) in women below age 45. This was less favourable than the trend in the general population, where IHD mortality fell by 9.7% in men and 8.3% in women of all ages, and by 31.1% (28.6, 33.5) in men and 40.5% (35.0, 45.5) in women under 45 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessing trends in cancer provides a means for gauging progress against the disease, estimating future demands for care and treatment, and suggesting clues about shifting causal factors that may account for the more recent changes.

The epidemiology of germ cell cancer of the ovary has been little investigated. We studied ovarian germ cell cancers incident 1971-84 in England, using data from the England and Wales national cancer register. The age distribution showed a sharp peak at ages 15-19, to which both teratomas and dysgerminomas contributed equally, and a secondary, much wider peak, at ages 65-69, mainly due to teratomas. For teratomas there were diverging secular trends by age: incidence has been increasing at ages 0-44 (P around 0.05) and decreasing at ages over 44 (P less than 0.01). Birth cohort analysis showed an increase in risk at ages 0-44 for more recent generations of women. There were no changes over time for dysgerminomas. There was no clear geographic pattern of distribution across the regions of England. The early age peak, and the increase in incidence of ovarian germ cell cancers at young ages but decrease at older ages, resembles testicular cancer epidemiology. Interestingly, discrepancies and similarities in the age distribution of these tumours between the sexes parallel lifetime profiles of gonadotropin levels in each sex.

The risk of testicular cancer in relation to lifetime histories of socioeconomic status, occupation, and occupational exposures was examined in a case-control study in England. Interviews were conducted with 259 cases, 238 control patients treated at radiotherapy and oncology centres, and 251 controls who were hospital inpatients in other departments. Risk of testicular cancer was raised in men of high socioeconomic status measured both by occupation and in other ways, and was similar in relation to status measured at birth and at various later stages of life. The occupations with highest risk of the tumour were paper and printing workers, professionals, and administrators. Exposures to various specific occupational agents that have been suggested in publications as potential risk factors were examined, but none showed an association with risk. The relative risk for occupational exposure to ionising radiation was 1.62 (95% confidence interval 0.83-3.17).

To determine whether the risk of Kaposi's sarcoma in patients with AIDS is increased by sexual contact with groups from abroad with a high incidence of Kaposi's sarcoma.

The distribution of cancers of the lung and stomach in the counties of England and Wales in 1968-81 was mapped, and compared to the distribution in the country in 1921-30 described by Stocks. The high risk of stomach cancer in North Wales noted by Stocks was found still to exist in each sex, although its disparity from the rest of the country has diminished. In general the geographic distribution of stomach cancer in both periods has paralleled that of post-neonatal mortality, at the same time and earlier, as an index of general poverty, but postneonatal mortality in North Wales has not been exceptionally high. In 1921-30 the highest risk of lung cancer was in and around London. In the modern data this was still true for older women, but for men and women under 45 years of age, and to a lesser extent for older men, the pattern has changed greatly; the epidemic has moved north, and highest risk is now in Northumberland and Durham. This spread appears to have occurred earlier for men than for women, and for urban than for rural areas, occurring latest of all for women in rural areas. Regional disparity has also increased, especially in males: risks in the northern regions are now over twice those in much of Wales and the South.

Mortality and cancer incidence were analysed in follow-up of a cohort of 3327 Vietnamese refugees who came to Britain after the end of the Vietnam war. Overall mortality of the refugees was very low compared to expectations based on England and Wales national rates: the all-cause standardized mortality ratio for males was 64 (95% confidence interval 52-77) and for females was 56 (95% confidence interval 44-71). This resulted particularly from very low mortality from ischaemic heart disease and colorectal cancer in each sex, and breast cancer in women. Mortality in the refugees was greatly increased for tuberculosis, cancer of the stomach in both sexes, cancers of the nasopharynx and liver in males, and peptic ulcer in females. Cancer incidence data showed in addition an excess of cancer of the penis. Despite the great trauma and stress of their flight, the only indication of a possible effect of the migration on the mortality of the refugees who survived to reach Britain was the excess of peptic ulcer deaths in women.

Melanocytic naevi (MN) are recognised risk factors for malignant melanoma but the epidemiology of MN is poorly understood. Some MN are present at birth and the study of congenital lesions is an important first step toward understanding the development of MN in early life. In this study, the prevalence and characteristics of congenital pigmented lesions were documented in 1012 White caucasian newborn babies at a maternity hospital in Oxford. Only 12 babies (1.2%) were found to have pigmented skin marks and each of these had only one lesion and no other abnormalities. MN were identified with certainty in only five babies (0.5% of the population; 95% CI, 0.06%-0.93%) thus confirming the relatively low prevalence of this lesion. Four of the MN were noted to be 'small' (less than 15 mm diameter) and all five were less than or equal to 20 mm in diameter. In other respects, the MN displayed a diversity of features. Of the other lesions there were two Mongolian blue spots, one melanocytic pustule, one 'probable' MN and three unusual skin marks where the diagnosis was uncertain but considered unlikely to be MN. During the course of the study, examinations were also carried out incidentally on 39 non-White babies. Twenty-two of these were noted to have Mongolian spots (57%) and three had other pigmented lesions (8%).

An analysis of the incidence of malignant melanoma according to occupation is presented using data from two national cancer registries. The data relate to 3991 cases of cutaneous malignant melanoma, 662 cases of ocular melanoma, and 179 cases of noncutaneous, non-ocular melanoma in subjects aged 15-64 in England and Wales diagnosed from 1971 to 1978 and to 5003 cases of cutaneous malignant melanoma diagnosed from 1961 to 1979 in Sweden in subjects born between 1896 and 1940. Professional workers of both sexes in both countries experienced an excess incidence of cutaneous malignant melanoma. An excess of ocular melanoma and of non-cutaneous, non-ocular melanoma also existed for this group in England and Wales. Pharmacists, medical doctors, and dentists had a high incidence of cutaneous melanoma in both countries and were represented three times when listing the top 20 occupations in both countries and both genders. Combining the data from cutaneous malignant melanoma over both sexes and both registries the occupations with the highest incidence ratios (expressed as a percentage) were: airline pilots, incidence ratio (IR) = 273, (95% confidence limits 118-538); finance and insurance brokers IR = 245 (140-398); professional accountants IR = 208 (134-307); dentists IR = 207 (133-309); inspectors and supervisors in transport IR = 206 (133-304); pharmacists IR = 198 (115-318); professionals not elsewhere classified IR = 196 (155-243); judges IR = 196 (126-289); doctors IR = 188 (140-248); university teachers IR = 188 (110-302); and chemists IR = 188 (111-296). No particular exposure in the workplace seemed to link these groups and only a few worked in high technology environments. Many of the highest risk groups have in common a high level of education. In England and Wales and in Sweden this might correlate particularly with foreign travel abroad was more unusual than it is now, but evidence on present and past exposure to sun by occupation is needed to clarify the reasons for the association.

Thymus cancer epidemiology has been little investigated, but recent clinical studies have suggested an association with the Epstein-Barr virus. We studied thymus cancer incidence 1963-83 and mortality 1959-86 in England and Wales, using data from the National Cancer Register and national mortality files. Mean age-standardised incidence rates of the tumour were 0.72 per million per annum for males and 0.64 for females; mortality rates were about half of this: 0.43 for males and 0.29 for females. There was no significant change in rates over time, nor any consistent pattern of risk by region of residence. Birth cohort analysis of mortality showed in each sex, lowest risk for persons born during the Second World War. The age distribution of the tumour was unusual: a progressive rise in both incidence and mortality rates occurred in each sex at ages up to 60-69, at which there was a striking peak, more marked for males and for incidence data, with a sharp decline thereafter. Immigrants from China and Cyprus had significantly high proportional registration ratios, but based on small numbers.

The relationship of risk of testis cancer, and subdivisions of the tumour by histology, to variables which may be related to hormonal status, sexual behaviour and fertility was investigated in data from a case-control study with 259 cases and 2 sets of controls. No consistent association was found between testis cancer risk and age at puberty, need to shave, obesity, alcohol intake, animal fat intake, and sexual behaviour. There was a significant excess of seminomas in very tall men. Testis cancer cases showed lower fertility than controls according to various measures, but this reflected the greater frequency of cryptorchidism among cases compared to controls. Among non-cryptorchid subjects there was no clear evidence that infertility was associated with risk of testis cancer.

For some death certificates in England and Wales the cause information coded and published in national data is not that initially submitted by the certifier, but instead derives from a subsequent enquiry to the certifier for further information. These enquiries can lead to substantial artefacts in secular mortality data, and also to substantial non-comparability between mortality data for special study groups, such as subjects in cohort studies, and published mortality data. A description of current enquiry policy relevant to cancers, and changes in this policy over recent years is given to aid interpretation of mortality data. The effects on secular data of changes in enquiry policy are illustrated. At 4-digit level of the ICD, changes in enquiry policy can alter published mortality rates by several hundred per cent. At 3-digit level the greatest effects of enquiries at present are to increase the number of deaths coded to cancer of the eye by 35% and cancer of the body of the uterus by 31%; cancers of the thymus, heart and mediastinum are increased by 18%, and pleural cancer by 17%, while decreases of more than 10% are caused for several 'other' and 'unspecified' rubrics, and a decrease of 6% for deaths coded to melanoma.

Data from the England and Wales national congenital malformation notification scheme were examined for associations of male genital tract malformations. For some of the malformations comparison of notification rates with the literature suggested gross undernotification. There was also evidence suggesting bias: examination of the relationships of the malformations to birth weight, maternal parity, and maternal age at delivery showed some highly significant trends in risk, most of which were at variance with findings in the literature, and several potential mechanisms for bias could be adduced. Direct investigation is needed, for this and other similar data sets, of the extent and mechanisms of biased undernotification.

Exposure to solar radiation is increasingly being associated with a risk of cutaneous melanoma, and some risk has also been attributed to exposure to fluorescent lights. The risk of cutaneous melanoma associated with exposure to some sources of artificial ultraviolet radiation was examined in a case-control study in a Scottish population with fairly low exposure to natural ultraviolet radiation. The risk was not significantly or consistently raised for exposure to fluorescent lights at home or at work. The use of ultraviolet lamps and sunbeds, however, was associated with a significantly increased risk (relative risk = 2.9; 95% confidence interval 1.3 to 6.4), and the risk was significantly related to duration of use. The risk was particularly raised among people who have first used [corrected] ultraviolet beds or lamps more than [corrected] five years before presentation (relative risk = 9.1; 95% confidence intervals 2.0-40.6), in whom it was significantly related to cumulative hours of exposure. The risks associated with exposure to ultraviolet lamps and sunbeds remained significant after adjustment for other risk factors for melanoma.

The relation of occupation to the risk of testicular cancer was investigated in a case-control study using data from the files of the South Thames Cancer Registry. Risks by age and histology subdivisions of the tumour were investigated since there is epidemiological evidence of differences in aetiology between these subdivisions but no previous systematic study of occupational risks by age and histology. Analyses were conducted comparing 1605 cases of testicular cancer incident in the region during 1958-77 with 7187 controls selected from other cancers incident in men in the region during the same period. The greatest risks of testicular cancer overall were for administrators and managers, sales workers, professional and allied workers, electrical workers, and clerical workers; these occupations were generally also at high risk of subdivisions of the tumour age and histology. Risk of testicular cancer overall and in each age and histology subgroup was greater in men of high than of low occupation based social class. Occupations with high risk of testicular cancer for their social class are of particular interest for further investigation of possible occupational risk factors; occupations with this characteristic for testicular cancer overall or in subdivisions in the present and some previous data are farmers, electrical workers, and paper and printing workers.

Counts of melanocytic naevi of 2 mm or greater diameter on all body sites were conducted in 197 Caucasian adults in Scotland. Mean naevus numbers were greater in young than in older adults, and in females than in males. Naevus counts on the upper limbs, lower limbs, and trunk were strongly and significantly correlated with each other and with whole body counts. Thus, where whole body counts are impractical, counting naevi at any of these individual sites should provide a satisfactory method for studying naevus distribution in large populations.

The position of the testes reduces their temperature but makes them vulnerable to trauma. Patients with testis cancer frequently report prior testicular trauma, but this trauma may have triggered diagnosis of the tumor rather than been aetiological. In this study, the frequencies of various prior traumatic and temperature exposures in 259 patients with testis cancer were compared with their frequencies in two sets of control patients who did not have testis cancer. Particular effort was made to prevent bias. Testis cancer was not significantly associated with any temperature or trauma exposure and the confidence limits of the findings excluded substantially raised risks. The evidence suggests that raised temperatures and traumas commonly encountered in everyday life are not important risk factors for testis cancer. The possible aetiological roles of extreme trauma sufficient to cause atrophy, and of the trauma and raised temperature which can occur in cryptorchidism, however, need investigation by other methods.

A case-control study of the aetiology of testicular cancer was conducted using information obtained by interview and from case-notes of 259 cases with testicular cancer and two sets of control patients -238 men with diagnoses other than testicular cancer attending the same radiotherapy centres as those attended by the cases, and 251 hospital in-patients not attending radiotherapy departments. Logistic regression analyses were performed, after stratifying by age and region of residence, to estimate the relative risks (RRs) associated with various aspects of prior medical history. The risk of testicular cancer was found to be raised for men with a history of cryptorchidism (RR based on comparison with all controls = 6.3; P less than 0.001), inguinal hernia (RR = 1.6; P = 0.14), mumps orchitis (RR = 12.7; P = 0.006), atopy (RR = 1.8; P = 0.03), and meningitis (RR = 3.0; P = 0.21). Inguinal herniorrhaphy before the age of 15 years was particularly a risk factor for seminoma, whereas the relative risks were similar for seminoma and teratoma for the other factors. The results add to the growing evidence that congenital abnormalities involving the process of testicular descent and closure of the processus vaginalis are risk factors for testicular cancer, and that some types of testicular damage later in life may also be important. The findings of associations with previous atopy and certain infections suggest a possible second aetiological mechanism - that immunological abnormalities may be associated with an increased risk of testis cancer.

In a study of risk factors for the development of melanocytic naevi in relation to the pathogenesis of malignant melanoma 197 white adults were examined by four dermatologists and naevus counts correlated with several other features. Highly significant associations were found between large numbers of banal acquired melanocytic naevi and the ability to tan easily without burning (skin types 3 and 4; relative risk 4.6), brown or hazel eyes (relative risk 3.5), green or grey eyes (relative risk 3.5) and brown or black hair (relative risk 3.7). No significant associations with numbers of naevi were shown for parity or use of oral contraceptives or other steroid hormones. This is the first study to find any relation between melanocytic naevi and phenotypic factors in a white population.

There is growing evidence that individuals at high risk of cutaneous melanoma can be identified by the use of simple measures of benign melanocytic naevi--raised risk occurring in persons who have large numbers of naevi, or naevi with atypical clinical features. Very high risk of melanoma appears to exist in two rare groups: persons with dysplastic naevi whose families include at least two individuals who have had melanoma, and persons with giant congenital naevi. Risks of melanoma in other individuals with dysplastic naevi and in persons with small congenital naevi have not yet been quantified. Much of the published work on risk of melanoma in relation to naevi has been based on clinical series or assemblage of case reports, with great potential for bias. In such studies, naevi have often been classified into dichotomies or syndromes originally defined for pathological or clinical purposes, frequently using poorly reproducible criteria. Case-control and cohort studies of the relationship of naevi to melanoma are needed, which use reproducible criteria and designs minimizing bias, and which examine risk in relation to graded clinical and histological measures of naevi.

In a case-control study of testis cancer 259 cases with testicular cancer, 238 controls treated at radiotherapy centres and 251 non-radiotherapy hospital in-patient controls were interviewed about some possible prenatal and familial risk factors for the tumour. For firstborn men, the risk of testis cancer increased significantly according to maternal age at the subject's birth, and this effect was most marked for seminoma. The association with maternal age was not apparent for cases other than firstborn. The risk of testis cancer was also significantly raised for men from small sibships and of early birth order. These results accord with the theory that raised maternal levels of available oestrogen during the early part of pregnancy are aetiological for testicular cancer in the son, although other explanations are possible; there is evidence that seminoma risk may particularly be affected.

Mortality and malignancy were studied in a series of 32 patients with xeroderma pigmentosum presenting during the period 1950-84. Twenty-nine of the patients were followed to the end of 1984 using the National Health Service Central Register, and hospital case records and correspondence with referring physicians; three patients had incomplete follow-up. Three of the patients developed malignant melanoma during follow-up, but none developed internal malignancy. Two males and one female died [standardized mortality ratio (SMR) = 971, P less than 0.05, for males; SMR = 1931, not significant, for females]. All three deaths were from non-malignant causes: severe neurological involvement with terminal infection. This high mortality from neurological complications in xeroderma pigmentosum patients contrasts with previously reported mortality, particularly from actinic-induced cutaneous tumours.

The month of birth of boys undergoing orchidopexy in the Oxfordshire Health District during the years 1974-83 was analysed. A significant seasonal variation with a peak in April was found for those boys operated upon by paediatric surgeons at a young age (0-4). Possible causes of this variation and its relationship to the aetiology of cryptorchidism are discussed.

Examination of 180 patients with cutaneous malignant melanoma and 197 control patients in a case-control study showed that the risk of melanoma is strongly related to numbers of benign melanocytic naevi (moles). Some unusual features of naevi--a diameter exceeding 7 mm, colour variation, and irregular lateral outline--also showed a strong association with the risk of melanoma, but the relation of numbers of naevi to risk was present even in the group of patients whose naevi had none of these unusual features. Biopsy of clinically atypical naevi from several of the patients at highest risk generally did not show dysplastic histology. Thus a group of people at high risk of melanoma may be identified by using simple clinical assessment of naevi.

The seasonality of presentation of 1019 skin melanomas in Oxford Region 1952-1975, and of 1,523 squamous cell and 4,865 basal cell skin cancers in the region 1967-1975, were analysed using data from the Oxford Cancer Registry. For males and for females, for each of the histologies there was a peak of presentations during July to September. In further subdivisions of the data by age and by skin site, a summer or autumn peak was generally present except where numbers of cases were small. Amplitude of seasonality did not show consistent differences by histology, sex, or skin site, but for both melanoma and squamous cell cancer amplitude was greater for persons aged under 55 years than for older persons. There was no substantial seasonality for presentations of cancers of all non-skin sites in the region. The seasonality of presentation of skin cancers appeared not to be mainly an artefact of the cancer registration process or of organisational aspects of medical care attendance, and only a small proportion of it could be explained as an artefact of the longer term increase in registrations of these cancers. The visibility of skin cancers might have lead to seasonal variation in rapidity of presentation to medical care, for instance for social reasons, or the results might reflect a short induction period effect of exposure to a seasonal insult, perhaps sun radiation, on the aetiology, growth or symptoms of skin cancers; for melanoma there is previous evidence suggesting a short induction period aetiological effect of sun radiation.

A study of cryptorchidism was undertaken based on patients identified through the Oxford Record Linkage Study. The cumulative lifetime incidence of archidopexy among males in the study area was estimated to be 3.38%; 88% of orchidopexies were performed on males aged 5 years and over and 32% on those aged 10 and over. In a case-control study with 146 cases ascertained at orchidopexy and 146 matched controls there was a substantially increased risk of cryptorchidism for those who had undergone breech labour. Raised risks of cryptorchidism were found for boys born to mothers who were primigravidas or aged under 20, and a significantly reduced risk was found for boys whose mothers were of B blood group. There was a gradient of increasing risk with decreasing birth weight and a significantly raised risk associated with clinical inguinal hernia. Since cryptorchidism and testicular cancer share several risk factors, it may be profitable to study newly identified risk factors for cryptorchidism in relation to testicular cancer.

Incidence of eye cancer in persons 15 years of age and over in England and Wales was studied as a surrogate for eye melanoma data. Age-standardized registration rates for cancer of the eye in adults increased by half in both males and females from 1962 to 1977. This probably reflects a real increase in incidence of eye melanoma. There was a gradient of increasing incidence with decreasingly urban place of residence, but there was no gradient of incidence with latitude. In both sexes, incidence was highest in the Birmingham region. Proportional registration ratios were generally higher for nonmanual than for manual social classes and notably high for electrical and electronics workers.

A case-control study is reported based on 87 deaths from testicular cancer that occurred in children in Great Britain 1953-73. Factors that significantly increased relative risk were tuberculosis of the mother during the index pregnancy and maternal epilepsy; factors that increased risk but not significantly were hyperemesis in the index pregnancy, a maternal history of stillbirths, and hernia and genitourinary defects in the child. Cryptorchidism was not studied. The available evidence suggests that prenatal determinants of testicular cancer in adults are also determinants of testicular cancer in childhood. The incidence and mortality from this disease are not increasing among children in Britain and other countries, whereas there is an increasing trend in young adults in several developed countries. Probably, therefore, the secular increase in the rates of young adult testicular cancer is due to factors that affect adults but not children, the hence are likely to be postnatal.

Part-time training of doctors with domestic commitments has taken place successfully in the Oxford region since 1966; 249 doctors have now passed through such training schemes and a further 120 are currently training part-time. Two training schemes are now offered for doctors at senior house officer and registrar level: one of six to eight sessions a week for those undertaking recognised training aiming for consultant or principal in general practice posts, the other of one to two sessions a week providing ad hoc training for those unable for personal reasons to follow a recognised training programme. For doctors at senior registrar level, part-time training entails five to eight sessions a week. Of the 115 doctors who have left the schemes and are now in career posts in the United Kingdom, 19% are now consultants, 30% in other hospital posts, 27% in general practice, and 18% are clinical medical officers; overall, 71% of those in career posts are working part-time. This experience shows that part-time training can be successful and that there is a continuing need for part-time career posts.

In most of England and Wales the incidence of malignant melanoma of the skin has risen rapidly in recent years, especially in women. Mean incidences in the 14 English health regions and Wales correlated negatively with latitude and positively with hours of sunshine, suggesting that exposure to sunshine was an important causal factor. Male and female incidences within a region tended to show similar yearly fluctuations, implying a common factor affecting the incidence in both men and women with a short latent period of action. This factor may be exposure to sunshine, which may cause melanoma after an induction period of about two years; for women the incidence of melanoma in the regions of England and Wales correlated positively with hours of sunshine two years earlier.