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

Author

Listed:
  • Michal Kovac

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford
    Research Group Human Genomics, University of Basel)

  • Carolina Navas

    (Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK)

  • Stuart Horswell

    (Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK)

  • Max Salm

    (Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK)

  • Chiara Bardella

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Andrew Rowan

    (Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK)

  • Mark Stares

    (Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK)

  • Francesc Castro-Giner

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Rosalie Fisher

    (Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK)

  • Elza C. de Bruin

    (University College London Cancer Institute and Hospitals)

  • Monika Kovacova

    (Faculty of Mechanical Engineering, Institute of Mathematics and Physics, Slovak University of Technology)

  • Maggie Gorman

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Seiko Makino

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Jennet Williams

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Emma Jaeger

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Angela Jones

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Kimberley Howarth

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • James Larkin

    (The Royal Marsden NHS Foundation Trust)

  • Lisa Pickering

    (The Royal Marsden NHS Foundation Trust)

  • Martin Gore

    (The Royal Marsden NHS Foundation Trust)

  • David L. Nicol

    (The Royal Marsden NHS Foundation Trust
    School of Medicine, University of Queensland)

  • Steven Hazell

    (The Royal Marsden NHS Foundation Trust)

  • Gordon Stamp

    (Experimental Histopathology, London Research Institute, Cancer Research UK)

  • Tim O’Brien

    (Urology Centre, Guy’s and St Thomas’s Hospital NHS Foundation Trust)

  • Ben Challacombe

    (Urology Centre, Guy’s and St Thomas’s Hospital NHS Foundation Trust)

  • Nik Matthews

    (Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK)

  • Benjamin Phillimore

    (Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK)

  • Sharmin Begum

    (Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK)

  • Adam Rabinowitz

    (Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK)

  • Ignacio Varela

    (Genomic analysis of tumour development, Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Universidad de Cantabria)

  • Ashish Chandra

    (Guy’s and St Thomas’s Hospital NHS Foundation Trust)

  • Catherine Horsfield

    (Guy’s and St Thomas’s Hospital NHS Foundation Trust)

  • Alexander Polson

    (Guy’s and St Thomas’s Hospital NHS Foundation Trust)

  • Maxine Tran

    (Uro-Oncology Research Group, University of Cambridge)

  • Rupesh Bhatt

    (University Hospitals)

  • Luigi Terracciano

    (Institute for Pathology, University Hospital Basel)

  • Serenella Eppenberger-Castori

    (Institute for Pathology, University Hospital Basel)

  • Andrew Protheroe

    (Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals)

  • Eamonn Maher

    (University of Cambridge)

  • Mona El Bahrawy

    (Imperial College London, Hammersmith Hospital)

  • Stewart Fleming

    (Medical Research Institute, University of Dundee Medical School, Ninewells Hospital)

  • Peter Ratcliffe

    (Hypoxia Biology Laboratory, Henry Wellcome Building for Molecular Physiology, University of Oxford)

  • Karl Heinimann

    (Research Group Human Genomics, University of Basel)

  • Charles Swanton

    (Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK
    University College London Cancer Institute and Hospitals)

  • Ian Tomlinson

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford
    NIHR Comprehensive Biomedical Research Centre, University of Oxford)

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.

Suggested Citation

  • Michal Kovac & Carolina Navas & Stuart Horswell & Max Salm & Chiara Bardella & Andrew Rowan & Mark Stares & Francesc Castro-Giner & Rosalie Fisher & Elza C. de Bruin & Monika Kovacova & Maggie Gorman , 2015. "Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7336
    DOI: 10.1038/ncomms7336
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