Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma

Abstract

Around half of high grade serous ovarian carcinomas (HGSOC) show homologous recombination repair deficiency (HRD), often caused by germline or somatic single nucleotide variant (SNV) mutations or small indels disrupting BRCA1/2. We have uniformly processed the largest collection of whole genome sequencing (WGS) data from HGSOC samples to date (N=205), comprehensively characterising the somatic mutational landscape, and expression at the BRCA1/2 loci. We discover that large structural variants (SV) are a frequent but unappreciated source of BRCA1/2 disruption in these tumours. Somatic structural variation at these loci is dominated by multi-megabase deletions that span the entirety of BRCA1 (median = 4.9Mb) or BRCA2 (median = 6.2Mb), independently affecting a substantial proportion of patients (16%) in addition to those affected by damaging germline or somatic short variants, within the BRCA1/2 coding sequences (24%). In common with previous studies, we show that the presence of damaging somatic SNVs or short indels in BRCA1 (OR=10, 95% CI 1.8-103, p=0.002, adj p=0.027 and BRCA2 (OR=17, 95% CI 2.1-816), p=0.002, adj.p=0.021) was found to influence HRD. For the first time we also study the compound effect of SV and SNV or short indel mutations at both loci, demonstrating that SVs often contribute to compound deficiencies involving SNVs or indels, with large somatic deletions contributing to these compound deficiencies in 15/205 (7%) of samples. Notably the strongest risk of HRD (OR=19 (2.4-896), p=6.6x10-3, adj P=8.5x10-3) is generated by combined large deletions at BRCA1 and BRCA2 in the absence of SNVs or indels, affecting 3% of patients. Overall, we show that HRD is a complex phenotype in HGSOC tumours, affected by the patterns of shorter variants such as SNVs and indels, SVs, methylation and expression seen at multiple loci, and we construct a successful (ROC AUC = 0.75) predictive model of HRD using such variables. In addition, HRD impacts patient survival when conferred by mechanisms other than through the well-understood short variants at BRCA1/2, currently exploited in the clinic. These results alter our understanding of the mutational landscape at the BRCA1/2 loci in highly rearranged tumours, and increase the number of patients predicted to benefit from therapies exploiting HRD in tumours such as PARP inhibition.