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

Ailith Ewing (Lead / Corresponding author), Alison Meynert, Michael Churchman, Graeme Grimes, Robert L. Hollis, C. Simon Herrington, Tzyvia Rye, Clare Bartos, Ian Croy, Michelle J. Ferguson, Mairi Lennie, Trevor McGoldrick, Neil McPhail, Nadeem Siddiqui, Suzanne Dowson, Rosalind Glasspool, Melanie Mackean, Fiona Nussey, Brian McDade, Darren Ennis, Lynn McMahon, Athena Matakidou, Brian A. Dougherty, Ruth March, J. Carl Barrett, Iain A. McNeish, Andrew V. Biankin, Patricia Roxburgh, Charlie Gourley, Colin A. Semple

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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 ¼ 205) together with matched RNA sequencing for the majority of tumors (N ¼ 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.

    Original languageEnglish
    Pages (from-to)3201-3214
    Number of pages14
    JournalClinical Cancer Research
    Issue number11
    Early online date19 Mar 2021
    Publication statusPublished - 1 Jun 2021

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research


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