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 struc...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60655-y |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ailith Ewing |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-52f679cd69484198a2dd0702f7d75564 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-52f679cd69484198a2dd0702f7d755642025-08-20T03:03:34ZengNature PortfolioNature Communications2041-17232025-07-0116111410.1038/s41467-025-60655-yDivergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancerAilith Ewing0Alison Meynert1Ryan Silk2Stuart Aitken3Devin P. Bendixsen4Michael Churchman5Stuart L. Brown6Alhafidz Hamdan7Joanne Mattocks8Graeme R. Grimes9Tracy Ballinger10Robert L. Hollis11C. Simon Herrington12John P. Thomson13Kitty Sherwood14Thomas Parry15Edward Esiri-Bloom16Clare Bartos17Ian Croy18Michelle Ferguson19Mairi Lennie20Trevor McGoldrick21Neil McPhail22Nadeem Siddiqui23Rosalind Glasspool24Melanie Mackean25Fiona Nussey26Brian McDade27Darren Ennis28The Scottish Genomes PartnershipLynn McMahon29Athena Matakidou30Brian Dougherty31Ruth March32J. Carl Barrett33Iain A. McNeish34Andrew V. Biankin35Patricia Roxburgh36Charlie Gourley37Colin A. Semple38MRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghNicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghNicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of EdinburghNicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of EdinburghCancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghNicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of EdinburghNicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of EdinburghDepartment of Oncology, Ninewells Hospital, NHS TaysideTayside Biorepository, School of Medicine, University of DundeeDepartment of Oncology, Aberdeen Royal InfirmaryDepartment of Oncology, Raigmore Hospital, NHS HighlandDepartment of Gynaecological Oncology, Glasgow Royal InfirmaryBeatson West of Scotland Cancer CentreEdinburgh Cancer Centre, Western General Hospital, NHS LothianEdinburgh Cancer Centre, Western General Hospital, NHS LothianSchool of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of GlasgowSchool of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of GlasgowPrecision Medicine Scotland (PMS-IC), Queen Elizabeth University HospitalOncology Translation and Big Data Mining, GSKTranslational Medicine, Oncology R&D, AstraZenecaPrecision Medicine, Oncology R&D, AstraZenecaTranslational Medicine, Oncology R&D, AstraZenecaBeatson West of Scotland Cancer CentreSchool of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of GlasgowBeatson West of Scotland Cancer CentreNicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghAbstract 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.https://doi.org/10.1038/s41467-025-60655-y |
| spellingShingle | 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 Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer Nature Communications |
| title | Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer |
| title_full | Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer |
| title_fullStr | Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer |
| title_full_unstemmed | Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer |
| title_short | Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer |
| title_sort | divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer |
| url | https://doi.org/10.1038/s41467-025-60655-y |
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