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

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. 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. ### Competing Interest Statement CG recieves research funding from AstraZeneca, MSD, Novartis, GSK, BerGen Bio, Medannex, Roche, Verastem, Artios and personal fees from AstraZeneca, MSD, GSK, Clovis, Verastem, Takeda, Eisai, Cor2Ed, Peer Voice. PR received honoraria from AstraZeneca. RH received consultancy fees from GSK and DeciBio.