UroToday - Numerous loci in the genome are associated with the risk of developing prostate cancer (CaP). Most of these associations however have not been correlated with clinical outcomes. Mutations in the breast cancer genes BRCA1 and BRCA2 are frequent in families with breast cancer and are associated with increased risk for breast and CaP in men.

Studies have suggested that the presence of a BRCA mutation may be associated with more aggressive CaP, but this has not been clearly demonstrated. In the online March 9, 2010 edition of Clinical Cancer Research , Dr. David Gallagher and colleagues from Memorial Sloan-Kettering Cancer Center confirm the association between more aggressive CaP and the presence of a BRCA germline mutation.

The study cohort was 832 CaP cases and 454 controls, all of Ashkenazi Jewish descent. This permitted targeted genotyping for founder mutations and blood was genotyped for the major Ashkenazi BRCA founder mutations BRCA1*185delAG and BRCA2*617delT . Single-nucleotide polymorphism (SNP) genotyping was performed using the Taqman assay. Data for clinical outcomes analysis were included only from men with localized disease at presentation. Patients were also stratified by Gleason score < 7 or > 7 for the analysis. Median age for controls and cases was 42 and 68 years, respectively. While BRCA1 mutations were similar for cases and controls, BRCA2 mutations were found in 2.4% of cases compared with 0.7% of controls. A BRCA2 mutation carried a 3.18 fold higher risk of CaP compared with non-carriers. Gleason score 7-10 tumors were found in 57% of non-carrier cases and in 85% of BRCA2 mutation cases, but there was no difference for BRCA1 cases and controls. After adjusting for age and stage, BRCA2 mutation carriers were twice as likely to have a Gleason score 7-10 CaP.

The study has a total of 7,254 person-years of follow-up and demonstrated 369 biochemical recurrences (BCR), 158 castrate metastases, and 184 deaths of which 98 were attributed to CaP. A carrier of a BRCA1 or BRCA2 mutation was at increased risk of BCR and death. BRCA2 mutation carriers had a greater risk of castrate metastases (HR 3.01) compared with non-carriers that resulted in a greater risk of death due to CaP (HR 5.48). BRCA1 mutation carriers also had an increased risk of death due to CaP (HR5.16).

Gallagher DJ, Gaudet MM, Pal P, Kirchhoff T, Balistreri L, Vora K, Bhatia J, Stadler Z, Fine SW, Reuter V, Zelefsky M, Morris MJ, Scher HI, Klein RJ, Norton L, Eastham JA, Scardino PT, Robson ME, Offit K
Clin Cancer Res . 2010 Apr 1;16(7):2115-21
doi: 10.1158/1078-0432.CCR-09-2871

UroToday Contributing Editor Christopher P. Evans, MD, FACS

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