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

• Published in: JCO precision oncology Vol. 7; p. e2300036
• Main Authors: Wineland, Dylane, Le, Anh N, Hausler, Ryan, Kelly, Gregory, Barrett, Emanuel, Desai, Heena, Wubbenhorst, Bradley, Pluta, John, Bastian, Paul, Symecko, Heather, D'Andrea, Kurt, Doucette, Abigail, Gabriel, Peter, Reiss, Kim A, Nayak, Anupma, Feldman, Michael, Domchek, Susan M, Nathanson, Katherine L, Maxwell, Kara N
• Format: Journal Article
• Language: English
• Published: United States 01.08.2023
• Subjects: BRCA1 Protein - genetics; BRCA2 Protein - genetics; Female; Homologous Recombination - genetics; Humans; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - epidemiology; Ovarian Neoplasms - genetics
• ISSN: 2473-4284
• DOI: 10.1200/PO.23.00036

Breast and ovarian tumors in germline 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 carriers. A clinically ascertained cohort of 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 carriers from The Cancer Genome Atlas (TCGA, n = 73) was used as a validation cohort. Ages of nonbreast/ovarian cancer diagnosis in germline carriers were similar to controls for the majority of cancer types. Nine of 45 (20%) primary nonbreast/ovarian tumors from germline carriers had biallelic loss of 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 loss compared with 22% ( < .001) of tumors without biallelic 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 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 mutations in selection of patients for platinum or PARP inhibitor therapy.