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Nat Commun. 2015 Mar 19;6:6336. doi: 10.1038/ncomms7336.

Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution.

Author information

1
1] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK [2] Department of Biomedicine, Research Group Human Genomics, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
2
Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
3
Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
4
Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
5
University College London Cancer Institute and Hospitals, Huntley Street, London WC1E 6DD, UK.
6
Faculty of Mechanical Engineering, Institute of Mathematics and Physics, Slovak University of Technology, Namestie slobody 17, 812 31 Bratislava, Slovakia.
7
Department of Medicine, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK.
8
1] Department of Urology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK [2] School of Medicine, University of Queensland, Brisbane, Australia.
9
Department of Histopathology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK.
10
Experimental Histopathology, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
11
Urology Centre, Guy's and St Thomas's Hospital NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
12
Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
13
Genomic analysis of tumour development, Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain.
14
Department of Histopathology, Guy's and St Thomas's Hospital NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
15
Department of Oncology, Uro-Oncology Research Group, University of Cambridge, Cambridge CB2 0RE, UK.
16
Department of Urology, University Hospitals, Birmingham B15 2TH, UK.
17
Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4003 Basel, Switzerland.
18
Department of Oncology, Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LJ, UK.
19
Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
20
Department of Histopathology, Imperial College London, Hammersmith Hospital, London W12 0HS, UK.
21
Department of Histopathology, Medical Research Institute, University of Dundee Medical School, Ninewells Hospital, Dundee DD1 9SY, UK.
22
Hypoxia Biology Laboratory, Henry Wellcome Building for Molecular Physiology, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
23
Department of Biomedicine, Research Group Human Genomics, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
24
1] Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK [2] University College London Cancer Institute and Hospitals, Huntley Street, London WC1E 6DD, UK.
25
1] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK [2] NIHR Comprehensive Biomedical Research Centre, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

Abstract

Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.

PMID:
25790038
PMCID:
PMC4383019
DOI:
10.1038/ncomms7336
[Indexed for MEDLINE]
Free PMC Article

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