Journal article

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

J-B Cazier, SR Rao, CM McLean, AL Walker, BJ Wright, EEM Jaeger, C Kartsonaki, L Marsden, C Yau, C Camps, P Kaisaki, J Taylor, JW Catto, IPM Tomlinson, AE Kiltie, FC Hamdy

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2014

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 associatio..

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Grants

Awarded by Wellcome Trust


Awarded by BBSRC


Awarded by MRC


Awarded by Biotechnology and Biological Sciences Research Council


Awarded by Cancer Research UK


Awarded by Medical Research Council


Awarded by National Institute for Health Research


Funding Acknowledgements

We are grateful to all the patients who agreed to participate in this study and to those who have provided their medical care. This work was supported by a grant from UCare to F.C.H., A.E.K., J.-B.C. and I.P.M.T., the Genomic Medicine and Surgical Innovation and Evaluation Themes of the Oxford NIHR Comprehensive Biomedical Research Centre, and core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z). We also wish to acknowledge the support of Andrew Roth with the Pyclone analysis. We thank Dr Selina Bhattarai, Consultant Histopathologist, Leeds Teaching Hospitals NHS Trust for outlining the IHC tumour areas, and Ms Katalin Karaszi for expert sectioning of the TMA and IHC advice.