Structural Variants at the Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma.

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

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2022;27(11):3201-3214

PMID: 33741650

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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 ( = 205) together with matched RNA sequencing for the majority of tumors ( = 150), we have comprehensively characterized mutation and expression at .

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 disruption in these tumors, and we found a genome-wide enrichment for large deletions at the 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 and 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.

Address: MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, Scotland, United Kingdom. [email protected].; MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, Scotland, United Kingdom.; Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, MRC IGMM, University of Edinburgh, Edinburgh, Scotland, United Kingdom.; Edinburgh Pathology, Cancer Research UK Edinburgh Centre, MRC IGMM, University of Edinburgh, Edinburgh, Scotland, United Kingdom.; Department of Oncology, Ninewells Hospital, NHS Tayside, Dundee, Scotland, United Kingdom.; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom.; Department of Oncology, Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom.; Institute of Education for Medical and Dental Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, Scotland, United Kingdom.; Department of Oncology, Raigmore Hospital, NHS Highland, Inverness, Scotland, United Kingdom.; Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom.; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom.; Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow, Scotland, United Kingdom.; Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Edinburgh, Scotland, United Kingdom.; Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, England, United Kingdom.; Precision Medicine Scotland (PMS-IC), Queen Elizabeth University Hospital, Glasgow, Scotland, United Kingdom.; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, England, United Kingdom.; Translational Medicine, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Precision Medicine, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom.; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom.; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales, Australia.

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

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MeSH Terms: BRCA1 Protein, BRCA2 Protein, Cystadenocarcinoma, Serous, Female, Gene Expression, Homologous Recombination, Humans, Mutation, Ovarian Neoplasms, Recombinational DNA Repair, Whole Genome Sequencing