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@article{Ewing:2021:10.1158/1078-0432.CCR-20-4068,
author = {Ewing, A and Meynert, A and Churchman, M and Grimes, GR and Hollis, RL and Herrington, CS and Rye, T and Bartos, C and Croy, I and Ferguson, M and Lennie, M and McGoldrick, T and McPhail, N and Siddiqui, N and Dowson, S and Glasspool, R and Mackean, M and Nussey, F and McDade, B and Ennis, D and McMahon, L and Matakidou, A and Dougherty, B and March, R and Barrett, JC and McNeish, IA and Scottish, Genomes Partnership and Biankin, AV and Roxburgh, P and Gourley, C and Semple, CA},
doi = {10.1158/1078-0432.CCR-20-4068},
journal = {Clinical Cancer Research},
pages = {3201--3214},
title = {Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma},
url = {http://dx.doi.org/10.1158/1078-0432.CCR-20-4068},
volume = {27},
year = {2021}
}

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TY  - JOUR
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 = 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.
AU  - Ewing,A
AU  - Meynert,A
AU  - Churchman,M
AU  - Grimes,GR
AU  - Hollis,RL
AU  - Herrington,CS
AU  - Rye,T
AU  - Bartos,C
AU  - Croy,I
AU  - Ferguson,M
AU  - Lennie,M
AU  - McGoldrick,T
AU  - McPhail,N
AU  - Siddiqui,N
AU  - Dowson,S
AU  - Glasspool,R
AU  - Mackean,M
AU  - Nussey,F
AU  - McDade,B
AU  - Ennis,D
AU  - McMahon,L
AU  - Matakidou,A
AU  - Dougherty,B
AU  - March,R
AU  - Barrett,JC
AU  - McNeish,IA
AU  - Scottish,Genomes Partnership
AU  - Biankin,AV
AU  - Roxburgh,P
AU  - Gourley,C
AU  - Semple,CA
DO  - 10.1158/1078-0432.CCR-20-4068
EP  - 3214
PY  - 2021///
SN  - 1078-0432
SP  - 3201
TI  - Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma
T2  - Clinical Cancer Research
UR  - http://dx.doi.org/10.1158/1078-0432.CCR-20-4068
UR  - http://hdl.handle.net/10044/1/88772
VL  - 27
ER  -

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