Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

Ailith Ewing (), Alison Meynert, Ryan Silk, Stuart Aitken, Devin P. Bendixsen, Michael Churchman, Stuart L. Brown, Alhafidz Hamdan, Joanne Mattocks, Graeme R. Grimes, Tracy Ballinger, Robert L. Hollis, C. Simon Herrington, John P. Thomson, Kitty Sherwood, Thomas Parry, Edward Esiri-Bloom, Clare Bartos, Ian Croy, Michelle Ferguson, Mairi Lennie, Trevor McGoldrick, Neil McPhail, Nadeem Siddiqui, Rosalind Glasspool, Melanie Mackean, Fiona Nussey, Brian McDade, Darren Ennis, Lynn McMahon, Athena Matakidou, Brian Dougherty, Ruth March, J. Carl Barrett, Iain A. McNeish, Andrew V. Biankin, Patricia Roxburgh, Charlie Gourley and Colin A. Semple
Additional contact information
Ailith Ewing: University of Edinburgh
Alison Meynert: University of Edinburgh
Ryan Silk: University of Edinburgh
Stuart Aitken: University of Edinburgh
Devin P. Bendixsen: University of Edinburgh
Michael Churchman: University of Edinburgh
Stuart L. Brown: University of Edinburgh
Alhafidz Hamdan: University of Edinburgh
Joanne Mattocks: University of Edinburgh
Graeme R. Grimes: University of Edinburgh
Tracy Ballinger: University of Edinburgh
Robert L. Hollis: University of Edinburgh
C. Simon Herrington: University of Edinburgh
John P. Thomson: University of Edinburgh
Kitty Sherwood: University of Edinburgh
Thomas Parry: University of Edinburgh
Edward Esiri-Bloom: University of Edinburgh
Clare Bartos: University of Edinburgh
Ian Croy: University of Edinburgh
Michelle Ferguson: NHS Tayside
Mairi Lennie: University of Dundee
Trevor McGoldrick: Aberdeen Royal Infirmary
Neil McPhail: NHS Highland
Nadeem Siddiqui: Glasgow Royal Infirmary
Rosalind Glasspool: Beatson West of Scotland Cancer Centre
Melanie Mackean: NHS Lothian
Fiona Nussey: NHS Lothian
Brian McDade: University of Glasgow
Darren Ennis: University of Glasgow
Lynn McMahon: Queen Elizabeth University Hospital
Athena Matakidou: GSK
Brian Dougherty: AstraZeneca
Ruth March: AstraZeneca
J. Carl Barrett: AstraZeneca
Iain A. McNeish: Beatson West of Scotland Cancer Centre
Andrew V. Biankin: University of Glasgow
Patricia Roxburgh: Beatson West of Scotland Cancer Centre
Charlie Gourley: University of Edinburgh
Colin A. Semple: University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. Here, we comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N = 324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we find high mtDNA mutation loads associated with shorter patient survival. We show that a combination of mutations in the mitochondrial and nuclear genomes impact prognosis, suggesting strategies for patient stratification.

Date: 2025
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DOI: 10.1038/s41467-025-60655-y

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