Tumor and germline next generation sequencing in high grade serous cancer: experience from a large population-based testing program

Abstract

The aim of this study was to determine the prevalence of somatic and germline pathogenic variants (PVs) in high-grade serous cancer (HGSC) and to demonstrate the technical feasibility and effectiveness of a large-scale, population-based tumor testing program. It involved a retrospective review of genetic test results in 600 consecutive HGSC tumor samples and a subsequent comparison of germline and tumor results in a subset of 200 individuals. Tumor testing was successful in 95% of samples (570/600) with at least one BRCA1/2 PV identified in 16% (93/570) of cases. Among the 200 paired cases, BRCA1/2 PVs were detected in 38 tumors (19%); 58% were somatic (22/38); and 42% were germline (16/38). There was 100% concordance between germline and tumor test results. This is the largest series of BRCA1/2 testing in HGSC (tumor-only and paired cohorts), reported to date, and our data show that an effectively designed and validated population-based tumor testing program can be used to determine both treatment eligibility and hereditary cancer risk.

Keywords: BRCA1/BRCA2; germline variant; high-grade serous cancer; next-generation sequencing; somatic variant; tumor testing.