Loss of Heterozygosity at the BRCA2 Locus Detected by Multiplex Ligation-Dependent Probe Amplification is Common in Prostate Cancers from Men with a Germline BRCA2 Mutation

Abstract

Purpose: Prostate cancer risk is increased for men carrying a pathogenic germline mutation in BRCA2, and perhaps BRCA1. Our primary aim was to test for loss of heterozygosity (LOH) at the locus of the mutation in prostate cancers from men who a carry pathogenic germline mutation in BRCA1 or BRCA2, and to assess clinical and pathologic features of these tumors. Experimental Design: From 1,243 kConFab families: (a) 215 families carried a pathogenic BRCA1 mutation, whereas 188 families carried a pathogenic BRCA2 mutation; (b) of the 158 men diagnosed with prostate cancer (from 137 families), 8 were confirmed to carry the familyspecific BRCA1 mutation, whereas 20 were confirmed to carry the family-specific BRCA2 mutation; and (c) 10 cases were eliminated from analysis because no archival material was available. The final cohort comprised 4 and 14 men with a BRCA1 and BRCA2 mutation, respectively. We examined LOH at the BRCA1 and BRCA2 genes using multiplex ligation-dependent probe amplification of DNA from microdissected tumor. Results: LOH at BRCA2 was observed in 10 of 14 tumors from BRCA2 mutation carriers (71%), whereas no LOH at BRCA1was observed in four tumors from BRCA1mutation carriers (P = 0.02). Under the assumption that LOH occurs only because the cancer was caused by the germline mutation, carriers of BRCA2 mutations are at 3.5-fold (95 % confidence interval, 1.8-12) increased risk of prostate cancer. A high Gleason was the only distinct clinical feature. Conclusions: These observations are consistent with the idea that BRCA2, but not BRCA1, is a tumor suppressor of prostate cancer.Prostate cancer, a common cancer diagnosed in Western men, is a major cause of morbidity and mortality. Risk factors include family history, especially if relatives are diagnosed at a young age (1). To date, the search for genes associated with a high individual risk has been unsuccessful, perhaps due to genetic heterogeneity. Studies are under way to find common genetic variants associated with a small increased risk (2).Rare germline mutations in the breast cancer predisposition genes, BRCA1 and, in particular, BRCA2, have been implicated in susceptibility to prostate cancer (3). The issue is complicated by the fact that, except in populations with founder mutations, only indirect estimates of the prevalence of germline mutations in unaffected men are available. These estimates have wide confidence intervals (that have not necessarily been correctly reported). The prevalence of BRCA2 mutations in selected series of men with prostate cancer is low, around 1% to 2%, but these estimates are imprecise (4, 5). In addition, estimates of penetrance from mutation testing case series have not been collected systematically and have used information from relatives (6), leading to potential biases. The best data have come from modified segregation analysis of mutation-carrying families identified from studying multiple-case breast and ovarian cancer families. These data suggest that the risk of prostate cancer is 4.7-fold highe...

Decreased Prostate Cancer-Specific Survival of Men with BRCA2 Mutations from Multiple Breast Cancer Families

“…13). Furthermore, this study confirmed our previously published data that loss of heterozygosity is observed in the tumor tissue of the majority of BRCA2 carriers (6). While this study demonstrates that a BRCA2 mutation is an independent factor in overall survival, it does so in a group of men unselected for family history.…”

“…Early studies estimated the relative risk for developing prostate cancer in men from BRCA2 mutation carrier families as being 2.9 to 4.8 (3)(4)(5), with some subgroups (men <65 years) having a relative risk as high as 7.3 (3). Later studies, estimated that men with a pathogenic BRCA2 mutation are at 3.5-fold (95% CI: 1.8-12) increased risk of developing prostate cancer (6). Furthermore, prostate cancers arising in BRCA2 mutation carriers display an aggressive tumor phenotype (6)(7) and present as more poorly differentiated tumors when compared with noncarrier prostate cancer controls (8).…”

“…Later studies, estimated that men with a pathogenic BRCA2 mutation are at 3.5-fold (95% CI: 1.8-12) increased risk of developing prostate cancer (6). Furthermore, prostate cancers arising in BRCA2 mutation carriers display an aggressive tumor phenotype (6)(7) and present as more poorly differentiated tumors when compared with noncarrier prostate cancer controls (8).…”

Skp2 Overexpression Is Associated with Loss of BRCA2 Protein in Human Prostate Cancer

“…2,3 The inheritance of one defective allele confers PCa predisposition; and neoplastic cells from predisposed individuals frequently exhibit loss of heterozygosity in the remaining wild-type allele, 4 consistent with a critical role of BRCA2 in prostate tumor suppression. The major identified function of the BRCA2 protein is to form complexes with Rad51 in the nuclei, which orchestrate homologous recombinational repair of double-stranded DNA breaks.…”

Germline Mutations in Predisposition Genes in Pediatric Cancer

“…28 These reports suggest that pathogenic mutations in BRCA1 and BRCA2 are more common in pediatric cancer than has been recognized previously and that they potentially underpin a broader spectrum of cancer phenotypes. [28][29][30][31][32][33][34][35][36][37][38] Family history is commonly used to identify persons with a possible heritable predisposition, especially within the pediatric cancer population. 39 However, only 40% of our patients with germline mutations that were pathogenic or probably pathogenic and that could be evaluated had a family history of cancer.…”