Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden

Jean Baptiste Cazier, S. R. Rao, C. M. McLean, A. L. Walker, B. J. Wright, E. E.M. Jaeger, C. Kartsonaki, L. Marsden, C. Yau, C. Camps, P. Kaisaki, J. Taylor, J. W. Catto, I. P.M. Tomlinson*, A. E. Kiltie, F. C. Hamdy, Christopher Allan, Moustafa Attar, John Bell, David BentleyJohn Broxholme, David Buck, Richard Copley, Richard Cornall, Peter Donnelly, Simon Fiddy, Angie Green, Lorna Gregory, Russell Grocock, Edouard Hatton, Chris Holmes, Linda Hughes, Peter Humburg, Sean Humphray, Alexander Kanapin, Zoya Kingsbury, Julian Knight, Sarah Lamble, Stefano Lise, Lorne Lonie, Gerton Lunter, Hilary Martin, Lisa Murray, Davis McCarthy, Gil McVean, Alistair Pagnamenta, Paolo Piazza, Guadelupe Polanco, Peter Ratcliffe, Andy Rimmer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former are not mutually exclusive with TP53 mutations or MDM2 amplification, showing that CDKN1A dysfunction is not simply an alternative mechanism for p53 pathway inactivation. We find strong positive associations between higher tumour stage/grade and greater clonal diversity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater diversity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression.

Original languageEnglish
Article number3756
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 29 Apr 2014

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