Biallelic <i>BRCA</i> Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline <i>BRCA1/2</i> Carriers.

Abstract

Breast and ovarian tumors in germline <i>BRCA1/2</i> carriers undergo allele-specific loss of heterozygosity, resulting in homologous recombination deficiency (HRD) and sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. This study investigated whether biallelic loss and HRD also occur in primary nonbreast/ovarian tumors that arise in germline <i>BRCA1/2</i> carriers. A clinically ascertained cohort of <i>BRCA1/2</i> carriers with a primary nonbreast/ovarian cancer was identified, including canonical (prostate and pancreatic cancers) and noncanonical (all other) tumor types. Whole-exome sequencing or clinical sequencing results (n = 45) were analyzed. A pan-cancer analysis of nonbreast/ovarian primary tumors from germline <i>BRCA1/2</i> carriers from The Cancer Genome Atlas (TCGA, n = 73) was used as a validation cohort. Ages of nonbreast/ovarian cancer diagnosis in germline <i>BRCA1/2</i> carriers were similar to controls for the majority of cancer types. Nine of 45 (20%) primary nonbreast/ovarian tumors from germline <i>BRCA1/2</i> carriers had biallelic loss of <i>BRCA1/2</i> in the clinical cohort, and 23 of 73 (32%) in the TCGA cohort. In the combined cohort, 35% and 27% of primary canonical and noncanonical BRCA tumor types, respectively, had biallelic loss. High HRD scores (HRDex > 42) were detected in 81% of tumors with biallelic <i>BRCA</i> loss compared with 22% (<i>P</i> < .001) of tumors without biallelic <i>BRCA</i> loss. No differences in genomic profile, including mutational signatures, mutation spectrum, tumor mutational burden, or microsatellite instability, were found in primary nonbreast/ovarian tumors with or without biallelic <i>BRCA1/2</i> loss. A proportion of noncanonical primary tumors have biallelic loss and evidence of HRD. Our data suggest that assessment of biallelic loss and HRD could supplement identification of germline <i>BRCA1/2</i> mutations in selection of patients for platinum or PARP inhibitor therapy.