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; The Scottish Genomes Partnership; Lynn McMahon; Athena Matakidou; Brian Dougherty; Ruth March; J. Carl Barrett; Iain A. McNeish; Andrew V. Biankin; Patricia Roxburgh; Charlie Gourley; Colin A. Semple

doi:10.1038/s41467-025-60655-y

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

Ailith Ewing (Lead / Corresponding author), 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 FergusonMairi Lennie, Trevor McGoldrick, Neil McPhail, Nadeem Siddiqui, Rosalind Glasspool, Melanie Mackean, Fiona Nussey, Brian McDade, Darren Ennis, The Scottish Genomes Partnership, Lynn McMahon, Athena Matakidou, Brian Dougherty, Ruth March, J. Carl Barrett, Iain A. McNeish, Andrew V. Biankin, Patricia Roxburgh, Charlie Gourley, Colin A. Semple

Cancer Research

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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.

Original language	English
Article number	5586
Number of pages	14
Journal	Nature Communications
Volume	16
Early online date	1 Jul 2025
DOIs	https://doi.org/10.1038/s41467-025-60655-y
Publication status	E-pub ahead of print - 1 Jul 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-025-60655-yLicence: CC BY

Final published versionFinal published version, 2.89 MBLicence: CC BY

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Ewing, A., Meynert, A., Silk, R., Aitken, S., Bendixsen, D. P., Churchman, M., Brown, S. L., Hamdan, A., Mattocks, J., Grimes, G. R., Ballinger, T., Hollis, R. L., Simon Herrington, C., Thomson, J. P., Sherwood, K., Parry, T., Esiri-Bloom, E., Bartos, C., Croy, I., ... Semple, C. A. (2025). Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer. Nature Communications, 16, Article 5586. Advance online publication. https://doi.org/10.1038/s41467-025-60655-y

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title = "Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer",

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.",

author = "Ailith Ewing and Alison Meynert and Ryan Silk and Stuart Aitken and Bendixsen, \{Devin P.\} and Michael Churchman and Brown, \{Stuart L.\} and Alhafidz Hamdan and Joanne Mattocks and Grimes, \{Graeme R.\} and Tracy Ballinger and Hollis, \{Robert L.\} and \{Simon Herrington\}, C. and Thomson, \{John P.\} and Kitty Sherwood and Thomas Parry and Edward Esiri-Bloom and Clare Bartos and Ian Croy and Michelle Ferguson and Mairi Lennie and Trevor McGoldrick and Neil McPhail and Nadeem Siddiqui and Rosalind Glasspool and Melanie Mackean and Fiona Nussey and Brian McDade and Darren Ennis and \{The Scottish Genomes Partnership\} and Lynn McMahon and Athena Matakidou and Brian Dougherty and Ruth March and \{Carl Barrett\}, J. and McNeish, \{Iain A.\} and Biankin, \{Andrew V.\} and Patricia Roxburgh and Charlie Gourley and Semple, \{Colin A.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = jul,

day = "1",

doi = "10.1038/s41467-025-60655-y",

language = "English",

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Ewing, A, Meynert, A, Silk, R, Aitken, S, Bendixsen, DP, Churchman, M, Brown, SL, Hamdan, A, Mattocks, J, Grimes, GR, Ballinger, T, Hollis, RL, Simon Herrington, C, Thomson, JP, Sherwood, K, Parry, T, Esiri-Bloom, E, Bartos, C, Croy, I, Ferguson, M, Lennie, M, McGoldrick, T, McPhail, N, Siddiqui, N, Glasspool, R, Mackean, M, Nussey, F, McDade, B, Ennis, D, The Scottish Genomes Partnership, McMahon, L, Matakidou, A, Dougherty, B, March, R, Carl Barrett, J, McNeish, IA, Biankin, AV, Roxburgh, P, Gourley, C & Semple, CA 2025, 'Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer', Nature Communications, vol. 16, 5586. https://doi.org/10.1038/s41467-025-60655-y

TY - JOUR

T1 - Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

AU - Ewing, Ailith

AU - Meynert, Alison

AU - Silk, Ryan

AU - Aitken, Stuart

AU - Bendixsen, Devin P.

AU - Churchman, Michael

AU - Brown, Stuart L.

AU - Hamdan, Alhafidz

AU - Mattocks, Joanne

AU - Grimes, Graeme R.

AU - Ballinger, Tracy

AU - Hollis, Robert L.

AU - Simon Herrington, C.

AU - Thomson, John P.

AU - Sherwood, Kitty

AU - Parry, Thomas

AU - Esiri-Bloom, Edward

AU - Bartos, Clare

AU - Croy, Ian

AU - Ferguson, Michelle

AU - Lennie, Mairi

AU - McGoldrick, Trevor

AU - McPhail, Neil

AU - Siddiqui, Nadeem

AU - Glasspool, Rosalind

AU - Mackean, Melanie

AU - Nussey, Fiona

AU - McDade, Brian

AU - Ennis, Darren

AU - The Scottish Genomes Partnership

AU - McMahon, Lynn

AU - Matakidou, Athena

AU - Dougherty, Brian

AU - March, Ruth

AU - Carl Barrett, J.

AU - McNeish, Iain A.

AU - Biankin, Andrew V.

AU - Roxburgh, Patricia

AU - Gourley, Charlie

AU - Semple, Colin A.

PY - 2025/7/1

Y1 - 2025/7/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105010291358

U2 - 10.1038/s41467-025-60655-y

DO - 10.1038/s41467-025-60655-y

M3 - Article

C2 - 40593568

AN - SCOPUS:105010291358

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 5586

ER -

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

Abstract

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