Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden.
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.
1] Bioinformatics Group, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK [2] Cancer Research UK, Oxford Cancer Research Centre, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
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JB
Cazier
1] Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK [2] Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
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SR
Rao
1] Cancer Research UK, Oxford Cancer Research Centre, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK [2] Gray Institute for Radiobiology and Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
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CM
McLean
A K
AK
Walker
1] Cancer Research UK, Oxford Cancer Research Centre, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK [2] Gray Institute for Radiobiology and Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
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AL
Walker
Bioinformatics and Statistical Genetics Core, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
B J
BJ
Wright
Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
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EE
Jaeger
Bioinformatics Group, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
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Kartsonaki
1] Cancer Research UK, Oxford Cancer Research Centre, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK [2] Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
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L
Marsden
Yau Group, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
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C
Yau
NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
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C
Camps
NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
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P
Kaisaki
NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
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J
Taylor
Academic Urology Unit, University of Sheffield, Sheffield S10 2JF, UK.
J W
JW
Catto
1] Cancer Research UK, Oxford Cancer Research Centre, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK [2] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK [3] NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK [4].
I P M
IP
Tomlinson
1] Cancer Research UK, Oxford Cancer Research Centre, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK [2] Gray Institute for Radiobiology and Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK [3].
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Kiltie
1] Cancer Research UK, Oxford Cancer Research Centre, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK [2] Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK [3].
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Hamdy
D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D014644:Genetic Variation; D016678:Genome / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D017422:Sequence Analysis, DNA; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
C493956:CDKN1A protein, human; D015820:Cadherins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C502403:FAT1 protein, human