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

• DOI: 10.1038/ncomms4756
• Publication Date: 2014-04-29T06:32:35Z
• Authors: J. -B. Cazier; S. R. Rao; C. M. McLean; A. K. Walker; B. J. Wright; E. E. M. Jaeger; C. Kartsonaki; L. Marsden; C. Yau; C. Camps; P. Kaisaki; ; Christopher Allan; Moustafa Attar; John Bell; David Bentley; John Broxholme; David Buck; Jean-Baptiste Cazier; 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; Natasha Sahgal; Jenny Taylor; Ian Tomlinson; Amy Trebes; Andrew Wilkie; Ben Wright; Chris Yau; J. Taylor; J. W. Catto; I. P. M. Tomlinson; A. E. Kiltie; F. C. Hamdy
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; 0301 basic medicine; Genome; Base Sequence; Molecular Sequence Data; Genetic Variation; Sequence Analysis, DNA; Cadherins; Article; 3. Good health; 03 medical and health sciences; Urinary Bladder Neoplasms; 616; Mutation; Humans; Neoplasm Grading

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 chromosomal changes in 14 bladder different grades stages. As well as detecting known cancer driver mutations, report identification recurrent protein-inactivating CDKN1A FAT1. The former not mutually exclusive with TP53 or MDM2 amplification, showing that dysfunction is simply an alternative mechanism for p53 pathway inactivation. We find strong positive associations between higher tumour stage/grade greater clonal diversity, number burden copy changes. In principle, sub-clones diversity and/or mutation within early-stage low-grade tumours could lesions high risk invasive progression.