BRCA1 and BRCA2 mutations predispose to select cancers, yet the interplay between germline and somatic BRCA alterations in driving tumorigenesis and conferring drug sensitivity remain poorly understood. To determine which tumors are dependent on mutant BRCA, we integrated the prospective clinical sequencing of germline blood and matched tumor specimens from 17,152 advanced cancer patients with zygosity analysis, broader somatic molecular features, and treatment outcomes. Tumor lineage dictated BRCA dependence in cancers of both the 2.7% of carriers with germline pathogenic variants and the 1.8% of patients with somatic loss-of-function mutations in BRCA1 and BRCA2 across 38 affected cancer types. The rate of biallelic inactivation of mutant BRCA1/2 varied by mutational origin and tumor lineage. Consequently, BRCA-mediated phenotypes such as homologous recombination deficiency (HRD) were associated with BRCA1/2 mutations in a cell type- and zygosity-dependent manner. Phenotypic penetrance was greatest in tumors of high-risk cancer types and in tumors with biallelic inactivation of mutant BRCA, independent of its germline or somatic origin. Conversely, heterozygous BRCA mutations in other cancer types conferred no HRD phenotype. These lineage-specific differences among hallmarks of BRCA dependence also predicted differential response to PARP-inhibitor therapy. Collectively, only BRCA mutations in tumors of high BRCA penetrance had a strong selective pressure for somatic biallelic inactivation, conferred dose-dependent somatic phenotypic consequences, and PARP inhibitor sensitivity. In contrast, BRCA1/2-mutant patients with cancers not traditionally associated with BRCA susceptibility generally had tumorigenesis independent of mutant BRCA. Overall, mutant BRCA was a founding pathogenic event on which some tumors depended while in others it was likely a dispensable and biologically neutral passenger mutation unrelated to tumorigenesis. This difference was conditioned by lineage, mutational origin, and zygosity, an understanding of which requires integrated germline and somatic molecular characterization in cancer patients with implications for screening, disease pathogenesis, clinical trial design, and therapy.

Citation Format: Philip Jonsson, Michael L. Cheng, Chaitanya Bandlamudi, Preethi Srinivasan, Shweta S. Chavan, Noah D. Friedman, Ezra Y. Rosen, Allison L. Richards, Nancy Bouvier, S. Duygu Selcuklu, Craig Bielski, Wassim Abida, Ahmet Zehir, Nikolaus Schultz, Mark T. Donoghue, Jose Baselga, Kenneth Offit, Marc Ladanyi, Eileen M. O’Reilly, Howard I. Scher, Zsofia K. Stadler, Mark E. Robson, David M. Hyman, Michael F. Berger, David B. Solit, Barry S. Taylor. BRCA-mediated tumorigenesis is origin and cell-type dependent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1752.