Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer
Author:
Ewing AilithORCID, Meynert Alison, Silk Ryan, Aitken Stuart, Bendixsen Devin P., Churchman Michael, Brown Stuart L., Hamdan Alhafidz, Mattocks Joanne, Grimes Graeme R., Ballinger Tracy, Hollis Robert L., Herrington C. Simon, Thomson John P., Sherwood Kitty, Parry Thomas, Esiri-Bloom Edward, Bartos Clare, Croy Ian, Ferguson Michelle, Lennie Mairi, McGoldrick Trevor, McPhail Neil, Siddiqui Nadeem, Glasspool Rosalind, Mackean Melanie, Nussey Fiona, McDade Brian, Ennis Darren, McMahon Lynn, Matakidou Athena, Dougherty Brian, March Ruth, Barrett J. Carl, McNeish Iain A.ORCID, Biankin Andrew V., Roxburgh Patricia, Gourley Charlie, Semple Colin A.,
Abstract
AbstractDeciphering 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. 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 novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification.
Publisher
Cold Spring Harbor Laboratory
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