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

Ewing, A. et al. (2021) Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma. Clinical Cancer Research, 27(11), pp. 3201-3214. (doi: 10.1158/1078-0432.CCR-20-4068) (PMID:33741650) (PMCID:PMC7610896)

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Purpose: 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. Experimental Design: Exploiting a large collection of whole-genome sequencing data from high-grade serous ovarian carcinoma (N = 205) together with matched RNA sequencing for the majority of tumors (N = 150), we have comprehensively characterized mutation and expression at BRCA1/2. Results: 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 BRCA1/2 disruption in these tumors, and we found a genome-wide enrichment for large deletions at the BRCA1/2 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 BRCA1 and BRCA2 in the absence of SSMs. Furthermore, these SVs are abundant and disruptive in other cancer types. Conclusions: 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Mcneish, Professor Iain and Glasspool, Dr Rosalind and Herrington, Professor Simon and Gourley, Prof Charlie and Ennis, Dr Darren and Roxburgh, Professor Patricia and Biankin, Professor Andrew and McDade, Mr Brian and McMahon, Mrs Lynn and Dowson, Miss Suzanne
Authors: Ewing, A., Meynert, A., Churchman, M., Grimes, G., Hollis, R. L., Herrington, C. S., Rye, T., Bartos, C., Croy, I., Ferguson, M. J., Lennie, M., McGoldrick, T., McPhail, N., Siddiqui, N., Dowson, S., Glasspool, R., Mackean, M., Nussey, F., McDade, B., Ennis, D., The Scottish Genomes Partnership, , McMahon, L., Matakidou, A., Dougherty, B. A., March, R., Barrett, J. C., Mcneish, I. A., Biankin, A. V., Roxburgh, P., Gourley, C., and Semple, C. A.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
ISSN (Online):1557-3265
Published Online:29 March 2021
Copyright Holders:Copyright © 2021 American Association for Cancer Research
First Published:First published in Clinical Cancer Research 27(11): 3201-3214
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
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190874CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)C596/A18076Institute of Cancer Sciences
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174160Precision PancAndrew BiankinCancer Research UK (CRUK)C29717/A23526CS -Translational Research Centre
170634Defining Platinum and PARP Responsive Molecular Phenotypes of Pancreatic Cancer.Andrew BiankinWellcome Trust (WELLCOTR)103721/Z/14/ZInstitute of Cancer Sciences