Journal Article

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

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

2025

Overview

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. Tumour evolution and heterogeneity in high grade serous ovarian cancer (HGSOC) remains poorly characterised. Here, the authors investigate the genomic landscape of HGSOC and reveal two distinct evolutionary trajectories associated with clinical outcomes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 631/337/1427 / 631/67/1517/1709 / 631/67/69 / 631/80/642/333 / 692/4028/67 / Cancer / Chromosomes / Chromothripsis / Cystadenocarcinoma, Serous - genetics / Cystadenocarcinoma, Serous - mortality / Cystadenocarcinoma, Serous - pathology / DNA damage / DNA, Mitochondrial - genetics / Evolution / Female / Gene expression / Genomes / Genomics / Heterogeneity / Homologous recombination / Homologous recombination repair / Humanities and Social Sciences / Humans / Medical prognosis / Mitochondrial DNA / multidisciplinary / Mutation / Neoplasm Grading / Ovarian cancer / Ovarian Neoplasms - genetics / Ovarian Neoplasms - mortality / Ovarian Neoplasms - pathology / Prognosis / Proteins / Science / Science (multidisciplinary) / Survival / Tumorigenesis / Tumors / Variation / Whole Genome Sequencing