Abstract
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 we aim to assess the prognostic utility of mutational signatures in ovarian high-grade serous carcinoma. 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). 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). 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. This study identifies the use of mutational signatures as a biomarker for survival outcome in ovarian high-grade serous carcinoma. Cancer Epidemiol Biomarkers Prev; 25(11); 1511-6. ©2016 AACR.
Highlights
Advances in sequencing technology and informatics have led to the identification of mutational signatures in human cancer [1]
Impact: This study identifies the use of mutational signatures as a biomarker for survival outcome in ovarian highgrade serous carcinoma
We develop a Bayesian statistical model to identify ovarian cancers that possess a BRCA1/2 mutational signature, and we evaluate the prognostic significance of this classification in two independent cohorts of high-grade ovarian serous carcinoma
Summary
Advances in sequencing technology and informatics have led to the identification of mutational signatures in human cancer [1]. These signatures are defined by the type and frequency of somatic events and represent a molecular phenotype of the underlying etiologic factors involved in cancer development. The most common mutational signature in human cancer shows an enrichment of C>T transitions at CpG sites, which reflect spontaneous deamination of methylated cytosine to thymine and has been associated with age. Mutational signatures have been identified by the broad sequencing of cancer genomes and reflect underlying processes of mutagenesis. We aim to assess the prognostic utility of mutational signatures in ovarian high-grade serous carcinoma
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