Abstract 3810: BRCA2 is a moderate penetrance gene contributing to young onset prostate cancer, but not disease over 65 years
Authors: Kote-Jarai Zsofia , Leongamornlert Daniel , Saunders Ed , Tymrakiewicz Malgorzata , Castro Elena , Mahmud Nadiya , Guy Michelle , Edwards Stephen , O'Brien Lynne , Hall Amanda , Wilkinson Rosemary , Goh Chee , Goldgar David ,   The UKGPC Collaborators, Easton Douglas , Eeles Rosalind 
Published: June 2012

Abstract
The aetiology of prostate cancer (PrCa) is poorly understood. A family history of prostate cancer, particularly at a young age, is a strong risk factor for the disease, indicating that inherited factors are important in PrCa. To date, the strongest genetic risk factor for PrCa is a protein truncating mutation in BRCA2, Studies in breast/ovarian cancer families have estimated a risk of ∼5 fold in BRCA2 carriers. We previously estimated that 2.3% of PrCa cases diagnosed at ≤55 years harbour a BRCA2 mutation. PrCa in BRCA2 carriers has been shown to be more aggressive, with poorer survival.
To further evaluate the role of BRCA2 in PrCa predisposition we screened 1910 men with PrCa aged 36 to 86 years. Patients were recruited through the UKGPCS (UK Genetic Prostate Cancer Study Collaborators). The study was enriched for cases with an early age of onset (1639 men ≤65yrs) and/or positive family history of PrCa (271 men &gt;65 with at least 2 affected relatives with PrCa). We analyzed the entire coding region of the BRCA2 gene in 46 PCR fragments by using a high-throughput multiplex fluorescent heteroduplex detection system developed for the ABI3130 genetic analyser. After repeats and QC 32 samples were excluded from the analysis. Fragments were analyzed for peak shifts corresponding to putative mutations in Genemapper v4.0 (Applied Biosystems) by visual inspection and using Bionumerics (Applied Maths). All fragments with peak-shifts were Sanger sequenced to characterise the mutation and validated using re-PCR and Sanger sequencing.
We have identified 19 frameshift mutations, 3 in-frame deletions and 56 missense variants of uncertain significance (UV). Based on studies in breast/ovarian cancer families, most UVs and some in-frame deletions are likely to be neutral. All the carriers of frameshift mutations were affected at age ≤65 years, 12 patients had family history of prostate cancer and 9 patients had some family history of breast or ovarian cancer. The prevalence of mutations was 1.25 % (8/638) for cases diagnosed ≤55 years and 1.17 % (19/1620) for cases diagnosed ≤ 65 years. Based on the estimated frequency of BRCA2 mutations in the UK (0.16%) we estimate that mutations in the BRCA2 gene confer a risk of prostate cancer of approximately 7 fold by age 65 (close to previous estimates from breast-ovarian cancer families), corresponding to an absolute risk of ∼4% by age 65.
As targeted treatments using drugs such as PARP inhibitors have shown activity in women with cancer who have BRCA mutations and as mutation tests become cheaper, there would be a rationale for testing young onset PrCa cases for BRCA2 mutations to offer such targeted treatments.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3810. doi:10.1158/1538-7445.AM2011-3810