Structural Variants at the <i>BRCA1/2</i> Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma.

Abstract

The abundance and effects of structural variation at BRCA1/2 in tumors are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated. Exploiting a large collection of whole-genome sequencing data from high-grade serous ovarian carcinoma (<i>N</i> = 205) together with matched RNA sequencing for the majority of tumors (<i>N</i> = 150), we have comprehensively characterized mutation and expression at <i>BRCA1/2</i>. In addition to the known spectrum of short somatic mutations (SSM), we discovered that multi-megabase structural variants (SV) were a frequent, unappreciated source of <i>BRCA1/2</i> disruption in these tumors, and we found a genome-wide enrichment for large deletions at the <i>BRCA1/2</i> loci across the cohort. These SVs independently affected a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring HRD and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both <i>BRCA1</i> and <i>BRCA2</i> in the absence of SSMs. Furthermore, these SVs are abundant and disruptive in other cancer types. These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification.