Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer
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.
Article Details
Authors (39)
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
Raigmore Hospital, Inverness, United Kingdom
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
Colin A. Semple