Finding genes that predispose to prostate cancer: the candidate approach based upon findings in BRCA2
Dr Ros Eeles MA; PhD; FRCP; FRCR, The Institute of Cancer Research

Finding genes that predispose to prostate cancer at the Institute of Cancer Research

The causes of prostate cancer (PC) are still not well understood, but there is strong evidence that a proportion of cases occur due to a genetic predisposition. Our former study funded by the Prostate Cancer Research Foundation showed that 2% of men who are diagnosed with PC at <55 years have germline mutations in the PC predisposition gene, BRCA2 and that there is a genotype/phenotype effect. The mutations or alterations that predispose to a high risk of PC, occur in a specific part of the gene. This area is downstream from the region called the ovarian cancer cluster region and we have postulated that there may be a ‘prostate cancer cluster region' in this gene. Following this discovery, we have started targeted PC screening in men who have germline mutations in BRCA2 and have anecdotal cases of extensive local PC discovered as a result of this approach. This has lead to the development of a EU-wide targeted screening study (the IMPACT study - Identification of Men with a genetic predisposition to Prostate cancer and their Clinical Treatment), involving 18 countries EU-wide. We have performed further research and have found that in PCs in men with a germline mutation in BRCA2 , about 40% of the time, the mutant copy of the gene is lost in the tumour, implying a gene dosage effect. We have also shown there is a halving of disease-free survival in PC cases who harbour germline mutations in BRCA2.

Despite the evidence that BRCA2 is a PC predisposing gene, it is a salutary fact that linkage analysis in 64 families from our laboratory did not identify the region within which the BRCA2 gene lies and neither has a meta analysis of 1139 PC families in an international consortium. Linkage studies lack power if the susceptibility alleles are relatively rare and/or confer moderate risks. Under these circumstances, a direct evaluation of a gene by association is required. Only a candidate approach identified hat BRCA2 is a high risk PC predisposition gene. Furthermore, using this approach in a founder population, NBS1 has now been found to have predisposing mutations. There is therefore a rationale for searching for candidate PC predisposition genes by a candidate approach by identifying candidates in (i) the DNA repair pathway and (ii) the pathway of interacting proteins which bind to the area of the BRCA2 protein coded for by the region within the gene which is mutated in early onset PC.

The discovery of alterations in genes that predispose to prostate cancer has several implications; it will: (i) enable the identification of those men at highest risk of the disease so that they can be offered targeted screening and preventions, (ii) highlight mechanisms of prostate cancer pathogenesis for scientific knowledge and targeted avoidance programmes ( e.g. avoidance of radiation) and (iii) enable molecular targets to be identified for development of new drugs for treatment and prevention.

Read the article published in Nature, 10 February 2008

Project commenced
June 2005

Length of project
2 years

Amount Supported
£159,619