Prostate Cancer Research
The UKGPCS (UK Genetic Prostate Cancer Study). Cancer Research UK/British Prostate Group/British Association of Urological Surgeons’ Section of Oncology Studies and the International ACTANE and PRACTICAL Consortium Studies
There is evidence that predisposition to prostate cancer has a genetic component. We interview prostate cancer cases presenting to The Royal Marsden NHS Foundation Trust to record their family history, and to determine the relative risk of clinically significant prostate cancer in relatives of cases. Clinical data are available about tumour parameters and response to treatment. Epidemiological data are collected via questionnaire in collaboration with Kenneth Muir, University of Warwick. Through an international collaboration (the ACTANE [Anglo/Canadian/Texan/
Australian/Norwegian/EUBiomed] consortium), more than 700 prostate cancer familial clusters have been identified and in collaboration with the International Consortium for Prostate Cancer Genetics genome wide linkage search has shown linkage evidence in 2000 families which is being followed up.
We have conducted a multistage GWAS in prostate cancer cases in collaboration with the UK screening study, ProtecT which has provided control s and have found numerous loci associated with prostate cancer. We are correlating these findings with new screening algorithms and clinical outcome.
We have undertaken candidate analyses and have found rare mutations in the DNA repair pathway in young onset prostate cancer cases. We plan to undertake exome and whole genome sequencing to identify further genetic changes. We have established an international consortium of over 30 prostate cancer case control studies with over 50 000 samples for validation of genetic variants.
Investigators: RA Eeles, Z Kote-Jarai, K Govindasami, M Guy, the Oncogenetics Team in collaboration with the Urology Unit; International ACTANE Consortium Collaboration with W Foulkes, J Simard, Canada; M Badzioch, C Amos, Texas, USA; L Maehle, P Moller, T Andersen, Norway; G Giles, J Hopper, G Severi, M Southey, Australia; DT Bishop, EU Biomed; and DF Easton and team at Cancer Research UK Genetic Epidemiology Unit Cambridge; over 300 UK Collaborators; British Prostate Group; British Association of Urological Surgeons’ Section of Oncology (BAUS). Epidemiological collaboration with Kenneth Muir and his team at University of Warwick. Collaboration with the ProtecT study investigators; D Neal, University of Cambridge; F Hamdy, University of Oxford; J Donovan, University of Bristol. International collaboration with International Consortium for Prostate Cancer Genetics and Lead of the PRACTICAL case control consortium.
External Funding: Cancer Research UK, Prostate Action, NIH, Tony Maxse/Hugh Knowles Fund, The FP7 Framework, NCRN, NIHR
Studies of Molecular Markers in Familial versus Sporadic Prostate Cancer Tumours
We have made tissue arrays from over 150 tumours from sporadic cases and young onset/ familial tumour arrays are in progress. New techniques have been developed to make arrays from prostate cancer biopsies and to collect fresh prostate tissue after radical prostatectomy. We are taking part in the International Cancer Genome Consortium (ICGC) to sequence prostate tumours and blood DNA. Molecular markers (some of which are developed from genetic associations in the studies above) are being assessed in body fluids in risk algorithms to target screening programmes.
Investigators: RA Eeles; in collaboration with DP Dearnaley, Urology Unit; C Cooper, Male Urological Cancer Research Centre; C Fisher, Department of Pathology; C Foster, University of Liverpool . Collaboration with Z Kote-Jarai, ICR; M Stratton and A Futreal, Sanger Centre; S Bova, Johns Hopkins USA; D Neal, University of Cambridge; S Hazell, Royal Marsden; C Foster, University of Liverpool; D Easton, University of Cambridge and the ICGC.
External Funding: CR-UK, NCRI, FP7; The Annabel Evans Memorial Fund
Gene–Environment Interaction Studies in Prostate Cancer
Environmental risk factors for prostate cancer development are being assessed by questionnaire to cover dietary, occupational, exercise, and sexual risk factors in prostate cancer cases. These will be correlated with genetic analyses to determine gene-environment interactions. Heavy metal levels will be measured from toenail clippings.
Investigators: RA Eeles, Z Kote-Jarai, K Govindasami, DP Dearnaley; in collaboration with K Muir, University of Warwick; T Key, University of Oxford; DF Easton, Cancer Research UK Genetic Epidemiology Unit, Cambridge; BAUS Section of Oncology
External Funding: Prostate Action, FP7; CR-UK
IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1 and BRCA2 mutation carriers and controls)
IMPACT, an international collaboration involving over 20 different countries, is the first international study to target PSA screening at high-risk individuals with an identified genetic alteration that is thought to predispose them to develop the disease. The study aims to assess the sensitivity, specificity and positive predictive value in this targeted group at increased prostate cancer risk. Pilot data have shown that there is an increased proportion of clinically significant disease in BRCA mutation carriers compared with population controls.
Investigators: RA Eeles, E Bancroft, E Castro, E Page, on behalf of the IMPACT steering committee and IMPACT collaborators
External Funding: The Ronald and Rita McAulay Foundation; CR- UK, International Funding to overseas collaborators.
More information about the study is available at the official IMPACT website. LOGO Image
Breast Cancer and Ovarian Cancer Screening Studies in High-Risk Individuals
Details of clinical studies in breast cancer predisposition gene carriers.
A UK Multicentre Study of MRI versus Mammography as a Screening Measure in Women at High Risk of Breast Cancer (MARIBS): The Interaction of Genetic Risk with Screening Parameters
We have coordinated a nationwide study of the comparison of breast magnetic resonance imaging (MRI) scans with mammography as a screening measure for unaffected breast cancer predisposition gene carriers or women at ≥50% risk of being a gene mutation carrier in high-risk families. Correlation between MRI outcome and genetic status is being analysed. A protocol to undertake whole body MRI screening in TP53 germline mutation carriers is in late stages of development by the MARIBS advisory committee.
Investigators: RA Eeles, F Lennard, G Kwan-Lim; Co-investigators D Easton, University of Cambridge; G Evans University of Manchester; S Gayther, S Ramus USC; R Warren, University of Cambridge; M Leach, Magnetic Resonance Group, The National MARIBS Advisory Group
External Funding: CR- UK, The Annabel Evans Memorial Fund