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

作者：Jean‐Baptiste Cazier, Srinivasa R. Rao, Chelsea McLean, Alexandra K. Walker, Ben Wright, E Jaeger, Christiana Kartsonaki, Luke Marsden, Christopher Yau, Carme Camps, Pamela J. Kaisaki, Christopher Allan, Moustafa Attar, John Bell, David L. Bentley, John Broxholme, David Buck, Jean‐Baptiste Cazier, Richard R. Copley, Richard J. 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 C. Knight, Sarah Lamble, Stefano Lise, Lorne Lonie, Gerton Lunter, Hilary C. Martin, Lisa Murray, Davis J. McCarthy, Gil McVean, Alistair T. Pagnamenta, Paolo Piazza, Guadelupe Polanco, Peter J. Ratcliffe, Andy Rimmer, Natasha Sahgal, Jenny C. Taylor, Ian Tomlinson, Ian Tomlinson, Amy Trebes, Andrew Wilkie, Ben Wright, Chris Yau, J. Taylor, James W.F. Catto, I. P. M. Tomlinson, I. P. M. Tomlinson, Anne E. Kiltie, Freddie C. Hamdy · 发表于：Nature Communications · 年份：2014 · DOI：10.1038/ncomms4756 · 被引用次数：115 · 研究领域：Bladder and Urothelial Cancer Treatments、Cancer Genomics and Diagnostics、Epigenetics and DNA Methylation

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.