The Institute of Cancer Research

Prostate Cancer Research

Translational Cancer Genetics Team

Section: Section of Cancer Genetics

 

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 Consortium Study

Investigators: RA Eeles, SM Edwards, Z Kote-Jarai, S Mulholland, S Bryant, A Ardern-Jones, A Hall, M Guy, B Gehr-Swain, L O'Brien, R Wilkinson, in collaboration with DP Dearnaley, Urology and Testicular Cancer Unit; International Consortium Collaboration with W Foulkes, J Simard, Canada; M Badzioch (now Seattle), Texas, USA; L Maehle, P Moller, T Andersen, Norway; G Giles, J Hopper, Australia; DT Bishop, EU Biomed; DF Easton, D Thompson Cancer Research UK Genetic Epidemiology Unit Cambridge; 350 UK Collaborators; British Prostate Group; British Association of Urological Surgeons Section of Oncology (BAUS)

External Funding: Cancer Research UK, The Prostate Cancer Research Foundation, NIH, Prostate Research Charity UK, Legacy of the Late Marion Silcock, Tony Maxse/Hugh Knowles Fund

There is evidence that predisposition to prostate cancer has a genetic component. We have interviewed over 2,600 symptomatic 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. About 15% of cases have a positive family history. We have also shown that variants in genes that influence VEGF expression and angiogenesis are associated with prostate cancer risk and prognosis. A polymorphism in the ATM  gene increases prostate cancer risk. Survival and late effects of treatment do not differ between the prostate cancer patients with and without a family history. Through an international collaboration (the ACTANE [Anglo/Canadian/Texan/
Australian/Norwegian/EUBiomed] consortium), more than 700 prostate cancer familial clusters have been identified and a 10cM genome wide linkage search has been completed in the largest 64 families. There are eight hints of linkage from this initial search and these will be followed up in the larger familial set. This is underway. Analysis of previously published candidate chromosomal regions has not shown any evidence of linkage to known loci in this familial set which predominantly consists of clinically detected disease. In collaboration with an International Consortium worldwide (The International Consortium for Prostate Cancer Genetics ICPCG) the largest linkage study in any common cancer has been undertaken in 1233 prostate cancer families which has revealed a LOD score of 3.57 at 22q which is being followed up. Through the UK collaboration, we have collected blood DNA samples from 2000 young onset prostate cancer cases diagnosed at <60 years. In the first 263 of these, we have found that 2.3% have a deleterious germline mutation in the gene, BRCA2 which confers a relative risk of 23-fold by the age of 60 years. The mutations were mainly 3' to the ovarian cancer cluster region in BRCA2 implying a genotype/phenotype effect. We have shown that variants of the GST P1 gene are associated with an increased prostate cancer risk in a proportion of this sample set, but that other GSTs (T/M), the LEPTIN gene, PSA gene and the selenium-dependent gene, GPX, are not.

  

 

 

Studies of Molecular Markers in Familial versus Sporadic Prostate Cancer Tumours

Investigators: S Jhavar, A Falconer, RA Eeles; in collaboration with DP Dearnaley, Urology and Testicular Cancer Unit; C Cooper, Section of Molecular Carcinogenesis; C Fisher, Department of Pathology; M Bailey, N Watkin K Anson C Corbishley St George’s Hospital; C Foster, Liverpool; J Hall, IARC, France

External Funding: The Community Fund, AICR, NCRI

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.

 

 

Gene–Environment Interaction Studies in Prostate Cancer

Investigators: RA Eeles, S Edwards, Z Kote-Jarai, DP Dearnaley; in collaboration with K Muir, University of Nottingham; T Key, University of Oxford; R Kirby, UCL; DF Easton, Cancer Research UK Genetic Epidemiology Unit, Cambridge; BAUS Section of Oncology

External Funding: The Prostate Cancer Research Foundation, Cancer Research UK

Environmental risk factors for prostate cancer development are being assessed by questionnaire to cover dietary, occupational, exercise, and sexual risk factors in 450 young onset prostate cancer cases presenting at <60 years of age. These will be correlated with genetic analyses (see project 'Studies of Molecular Markers in Familial versus Sporadic Prostate Cancer Tumours'). Selenium levels will be measured from toenail clippings.

 

 

 

IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1 and BRCA2 mutation carriers and controls)

Investigators: RA Eeles, E Bancroft, A Mitra, on behalf of the IMPACT steering committee and IMPACT collaborators

External Funding: Cancer Research UK, The McAulay Fellowship; A & S Cliff.

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.

More information about the study is available at the official IMPACT website.

 

 

 

AIDIT (Advancing International Co-operation and Developing Infrastructure for Targeted Screening of Prostate Cancer in Men with Genetic Predisposition)

Investigators: R A Eeles, E Bancroft, A Mitra, M Christie, R Doherty, S Morgan in collaboration with G Luleci, E Manguoglu, Akdeniz University, Turkey; J Lubinski, K Zieba International Hereditary Cancer Centre, Pomeranian Medical University, Poland, on behalf of the IMPACT steering committee

External Funding: European Comission (Framework 6 Programme).

An EC Framework 6 Project which will facilitate the inclusion of research centres from the EC’s Associated Candidate Countries (Turkey, Romania and Bulgaria in particular) and New Member States in the International IMPACT study.