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

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, Seiko Makino, Jennet Williams, Emma Jaeger, Angela Jones, Kimberley Howarth, James Larkin, Lisa Pickering, Martin Gore, David L. Nicol, Steven Hazell, Gordon Stamp, Tim O’Brien, Ben Challacombe, Nik Matthews, Benjamin Phillimore, Sharmin Begum, Adam Rabinowitz, Ignacio Varela, Ashish Chandra, Catherine Horsfield, Alexander Polson, Maxine Tran, Rupesh Bhatt, Luigi Terracciano, Serenella Eppenberger-Castori, Andrew Protheroe, Eamonn Maher, Mona El Bahrawy, Stewart Fleming, Peter Ratcliffe, Karl Heinimann, Charles Swanton () and Ian Tomlinson ()
Additional contact information
Michal Kovac: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford
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
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
Ian Tomlinson: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7336

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