A BRCA1/2 Mutational Signature and Survival in Ovarian High-Grade Serous Carcinoma

Background: Mutational signatures have been identified by the broad sequencing of cancer genomes and reflect underlying processes of mutagenesis. The clinical application of mutational signatures is not well defined. Here weaim to assess the prognostic utility of mutational signatures in ovarian high-grade serous carcinoma. Methods: Open access data of 15,439 somatic mutations of 310 ovarian high-grade serous carcinomas from The Cancer Genome Atlas (TCGA) are used to construct a Bayesian model to classify each cancer as either having or lacking a BRCA1/2 mutational signature. We evaluate the association of the BRCA1/2 signature with overall survival on the TCGA dataset and on an independent cohort of 92 ovarian high-grade serous carcinomas from the Australian Ovarian Cancer Study (AOCS). Results: Patients from TCGA with tumors harboring the BRCA1/2 mutational signature have improved survival (55.2 months vs. 38.0 months), which is independent of BRCA1/2 gene mutation status, age, stage, and grade (HR = 0.64; P = 0.02). In the AOCS dataset, the BRCA1/2 mutational signature is also associated with improved overall survival (46.3 months vs. 23.6 months) independent of age and stage (HR = 0.52; P = 0.007). Conclusions: A BRCA1/2 mutational signature is a prognostic marker in ovarian high-grade serous carcinoma. Mutational signature analysis of ovarian cancer genomes may be useful in addition to testing for BRCA1/2 mutations. Impact: This study identifies the use of mutational signatures as a biomarker for survival outcome in ovarian high-grade serous carcinoma. (C) 2016 AACR.