RT Journal Article
SR Electronic
T1 Copy-number signatures and mutational processes in ovarian carcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 174201
DO 10.1101/174201
A1 Geoff Macintyre
A1 Teodora E. Goranova
A1 Dilrini De Silva
A1 Darren Ennis
A1 Anna M. Piskorz
A1 Matthew Eldridge
A1 Daoud Sie
A1 Liz-Anne Lewsley
A1 Aishah Hanif
A1 Cheryl Wilson
A1 Suzanne Dowson
A1 Rosalind M. Glasspool
A1 Michelle Lockley
A1 Elly Brockbank
A1 Ana Montes
A1 Axel Walther
A1 Sudha Sundar
A1 Richard Edmondson
A1 Geoff D. Hall
A1 Andrew Clamp
A1 Charlie Gourley
A1 Marcia Hall
A1 Christina Fotopoulou
A1 Hani Gabra
A1 James Paul
A1 Anna Supernat
A1 David Millan
A1 Aoisha Hoyle
A1 Gareth Bryson
A1 Craig Nourse
A1 Laura Mincarelli
A1 Luis Navarro Sanchez
A1 Bauke Ylstra
A1 Mercedes Jimenez-Linan
A1 Luiza Moore
A1 Oliver Hofmann
A1 Florian Markowetz
A1 Iain A. McNeish
A1 James D. Brenton
YR 2017
UL http://biorxiv.org/content/early/2017/08/09/174201.abstract
AB Tumours with profound copy-number aberration elude molecular stratification due to their genomic complexity. By representing this complexity as a mixture of copy-number signatures, we provide molecular explanations for differing clinical outcomes. Here we present a method for copy-number signature identification, deriving eight signatures in 117 shallow whole-genome sequenced high-grade serous ovarian cancers (HGSOC), which validated on independent cohorts of 95 deep whole-genome sequenced, and 402 SNP array-profiled cases. Three copy-number signatures predicted longer overall survival, while the others predicted poorer outcome. We found evidence for the mutational processes giving rise to copy-number change for six of the eight signatures via correlations with other genomic features. Our results provide insights into the pathogenesis of HGSOC by uncovering multiple mutational processes that shape genomes following TP53 mutation. Importantly, our work shows that most HGSOC have a mixture of mutational processes suggesting that targeting a single mutator phenotype may be therapeutically suboptimal.