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

^{1 1}Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab), Research Department, Peter MacCallum Cancer Centre; ²Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre; and ³Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Victoria, Australia; ⁴Department of Anatomical Pathology, Sullivan Nicolaides Pathology, Taringa, Queensland, Australia; and ⁵Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada

^* To whom correspondence should be addressed. E-mail: Heather.Thorne{at}petermac.org.

	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 family-specific 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 BRCA1 was observed in four tumors from BRCA1 mutation 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.

Key Words: BRCA1, BRCA2, loss of heterozygosity, multiplex ligation-dependent probe amplification, prostate cancer