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

Ailith Ewing; 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

doi:10.1158/1078-0432.CCR-20-4068

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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Abstract

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 language	English
Pages (from-to)	3201-3214
Number of pages	14
Journal	Clinical Cancer Research
Volume	27
Issue number	11
Early online date	19 Mar 2021
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-4068
Publication status	Published - 1 Jun 2021

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1078-0432.CCR-20-4068

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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., ... Semple, C. A. (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), 3201-3214. https://doi.org/10.1158/1078-0432.CCR-20-4068

@article{2af778265dc24034a633d3e690388069,

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

abstract = "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.",

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

note = "Copyright {\textcopyright}2021, American Association for Cancer Research",

year = "2021",

month = jun,

day = "1",

doi = "10.1158/1078-0432.CCR-20-4068",

language = "English",

volume = "27",

pages = "3201--3214",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "11",

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Ewing, A, Meynert, A, Churchman, M, Grimes, G, Hollis, RL, Herrington, CS, Rye, T, Bartos, C, Croy, I, Ferguson, MJ, Lennie, M, McGoldrick, T, McPhail, N, Siddiqui, N, Dowson, S, Glasspool, R, Mackean, M, Nussey, F, McDade, B, Ennis, D, University of Edinburgh, McMahon, L, Matakidou, A, Dougherty, BA, March, R, Barrett, JC, McNeish, IA, Biankin, AV, Roxburgh, P, Gourley, C & Semple, CA 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, vol. 27, no. 11, pp. 3201-3214. https://doi.org/10.1158/1078-0432.CCR-20-4068

TY - JOUR

T1 - Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma

AU - Ewing, Ailith

AU - Meynert, Alison

AU - Churchman, Michael

AU - Grimes, Graeme

AU - Hollis, Robert L.

AU - Herrington, C. Simon

AU - Rye, Tzyvia

AU - Bartos, Clare

AU - Croy, Ian

AU - Ferguson, Michelle J.

AU - Lennie, Mairi

AU - McGoldrick, Trevor

AU - McPhail, Neil

AU - Siddiqui, Nadeem

AU - Dowson, Suzanne

AU - Glasspool, Rosalind

AU - Mackean, Melanie

AU - Nussey, Fiona

AU - McDade, Brian

AU - Ennis, Darren

AU - McMahon, Lynn

AU - Matakidou, Athena

AU - Dougherty, Brian A.

AU - March, Ruth

AU - Barrett, J. Carl

AU - McNeish, Iain A.

AU - Biankin, Andrew V.

AU - Roxburgh, Patricia

AU - Gourley, Charlie

AU - Semple, Colin A.

PY - 2021/6/1

Y1 - 2021/6/1

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-20-4068

DO - 10.1158/1078-0432.CCR-20-4068

M3 - Article

C2 - 33741650

SN - 1078-0432

VL - 27

SP - 3201

EP - 3214

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 11

ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

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