Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8þ) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3 0 region of BRCA2 (c.7914þ) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR ¼ 1.78; 95% confidence interval (CI), 1.25-2.52; P ¼ 0.001], as well as elevated risk of Gleason 8þ prostate cancer (HR ¼ 3.11; 95% CI, 1.63-5.95; P ¼ 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR ¼ 2.83; 95% CI, 1.71-4.68; P ¼ 0.00004) and elevated risk of Gleason 8þ prostate cancer (HR ¼ 4.95; 95% CI, 2.12-11.54; P ¼ 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer.Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Prostate Cancer Risk by BRCA2 Genomic Regions

“…This corresponds to a significantly higher PCa risk associated with PVs in the PCCR than PVs not in the PCCR (HR = 2.34, 95% CI 1.09–5.03; Table 1 ). Compared with PVs in the region c.1001 to c.7913 [8] , PCCR PVs were associated with an HR of 2.09 (95% CI 0.98–4.45). As previously reported, the SIR for carriers of PVs in the wide definition of the OCCR ( n = 178) was 2.46 (95% CI 1.07–5.64) [1] , and the risk for carriers of PCCR PVs was also significantly higher than that for OCCR PV carriers (HR = 3.41, 95% CI 1.27–9.16).…”

“…PVs in the OCCR have consistently been shown to be associated with an increased ovarian cancer risk but a decreased breast cancer risk [2] , [3] , [5] , [6] , although the precise boundaries of the OCCR [3] , [5] and the mechanisms behind this risk variation remain uncertain. It has been proposed that the likelihood that a PV triggers nonsense-mediated mRNA decay varies by genomic region [7] , [8] so that OCCR PVs might produce a truncated or alternatively spliced protein the capability of which to suppress tumours varies by cancer type [2] , [3] , [5] , [7] , [8] , but there is currently no experimental support for this hypothesis [7] . Shortly after the publication of our manuscript, Patel and coworkers [8] proposed the existence of a prostate cancer cluster region (PCCR) at the 3′ end of BRCA2 , based on retrospective cohort data.…”

“…It has been proposed that the likelihood that a PV triggers nonsense-mediated mRNA decay varies by genomic region [7] , [8] so that OCCR PVs might produce a truncated or alternatively spliced protein the capability of which to suppress tumours varies by cancer type [2] , [3] , [5] , [7] , [8] , but there is currently no experimental support for this hypothesis [7] . Shortly after the publication of our manuscript, Patel and coworkers [8] proposed the existence of a prostate cancer cluster region (PCCR) at the 3′ end of BRCA2 , based on retrospective cohort data. This retrospective study reported that men with BRCA2 PVs in the proposed PCCR have a higher risk of PCa (hazard ratio [HR] = 1.78, 95% confidence interval [CI] 1.25–2.52), particularly Gleason score ≥8 PCa (HR = 3.11, 95% CI 1.63–5.95), than men with PVs in the reference region c.1001 to c.7913, but did not present estimates of the absolute PCa risk for PCCR PV carriers [8] .…”

“…Shortly after the publication of our manuscript, Patel and coworkers [8] proposed the existence of a prostate cancer cluster region (PCCR) at the 3′ end of BRCA2 , based on retrospective cohort data. This retrospective study reported that men with BRCA2 PVs in the proposed PCCR have a higher risk of PCa (hazard ratio [HR] = 1.78, 95% confidence interval [CI] 1.25–2.52), particularly Gleason score ≥8 PCa (HR = 3.11, 95% CI 1.63–5.95), than men with PVs in the reference region c.1001 to c.7913, but did not present estimates of the absolute PCa risk for PCCR PV carriers [8] . In order to substantiate or refute this association, and to provide direct estimates of the absolute risk of PCa for carriers of BRCA2 PCCR PVs, we have reanalysed our prospective data.…”

“…Detailed information on the cohort and on inclusion criteria, data collection, follow-up, and statistical analysis approach is available in our recent publication [1] . The participants’ PVs (listed in Supplementary Table S1) were grouped on the basis of position within the BRCA2 gene, based on the proposed PCCR (c.7914 to 3′ [8] ; HGVS nomenclature [ http://varnomen.hgvs.org/ ]; using cDNA reference sequence NM_000059.3 and reference genome hg18) and the wide definition of the OCCR (c.2831 to c.6401) [1] , [2] , [3] , [4] . We additionally considered the region bounded by c.756 and c.1000 in which Patel and coworkers [8] found evidence of an increased PCa risk, but due to a small sample size ( n = 1) we could not estimate the PCa risk associated with this region.…”