title: Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution.
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.
authors: 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.
authors: Michal
authors: M
authors: Kovac
authors: Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Carolina
authors: C
authors: Navas
authors: Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Stuart
authors: S
authors: Horswell
authors: Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Max
authors: M
authors: Salm
authors: 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.
authors: Chiara
authors: C
authors: Bardella
authors: Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Andrew
authors: A
authors: Rowan
authors: Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Mark
authors: M
authors: Stares
authors: 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.
authors: Francesc
authors: F
authors: Castro-Giner
authors: Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Rosalie
authors: R
authors: Fisher
authors: University College London Cancer Institute and Hospitals, Huntley Street, London WC1E 6DD, UK.
authors: Elza C
authors: EC
authors: de Bruin
authors: Faculty of Mechanical Engineering, Institute of Mathematics and Physics, Slovak University of Technology, Namestie slobody 17, 812 31 Bratislava, Slovakia.
authors: Monika
authors: M
authors: Kovacova
authors: 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.
authors: Maggie
authors: M
authors: Gorman
authors: 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.
authors: Seiko
authors: S
authors: Makino
authors: 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.
authors: Jennet
authors: J
authors: Williams
authors: 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.
authors: Emma
authors: E
authors: Jaeger
authors: 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.
authors: Angela
authors: A
authors: Jones
authors: 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.
authors: Kimberley
authors: K
authors: Howarth
authors: Department of Medicine, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK.
authors: James
authors: J
authors: Larkin
authors: Department of Medicine, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK.
authors: Lisa
authors: L
authors: Pickering
authors: Department of Medicine, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK.
authors: Martin
authors: M
authors: Gore
authors: 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.
authors: David L
authors: DL
authors: Nicol
authors: Department of Histopathology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK.
authors: Steven
authors: S
authors: Hazell
authors: Experimental Histopathology, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Gordon
authors: G
authors: Stamp
authors: Urology Centre, Guy's and St Thomas's Hospital NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
authors: Tim
authors: T
authors: O'Brien
authors: Urology Centre, Guy's and St Thomas's Hospital NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
authors: Ben
authors: B
authors: Challacombe
authors: Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Nik
authors: N
authors: Matthews
authors: Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Benjamin
authors: B
authors: Phillimore
authors: Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Sharmin
authors: S
authors: Begum
authors: Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Adam
authors: A
authors: Rabinowitz
authors: 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.
authors: Ignacio
authors: I
authors: Varela
authors: Department of Histopathology, Guy's and St Thomas's Hospital NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
authors: Ashish
authors: A
authors: Chandra
authors: Department of Histopathology, Guy's and St Thomas's Hospital NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
authors: Catherine
authors: C
authors: Horsfield
authors: Department of Histopathology, Guy's and St Thomas's Hospital NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
authors: Alexander
authors: A
authors: Polson
authors: Department of Oncology, Uro-Oncology Research Group, University of Cambridge, Cambridge CB2 0RE, UK.
authors: Maxine
authors: M
authors: Tran
authors: Department of Urology, University Hospitals, Birmingham B15 2TH, UK.
authors: Rupesh
authors: R
authors: Bhatt
authors: Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4003 Basel, Switzerland.
authors: Luigi
authors: L
authors: Terracciano
authors: Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4003 Basel, Switzerland.
authors: Serenella
authors: S
authors: Eppenberger-Castori
authors: Department of Oncology, Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LJ, UK.
authors: Andrew
authors: A
authors: Protheroe
authors: Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
authors: Eamonn
authors: E
authors: Maher
authors: Department of Histopathology, Imperial College London, Hammersmith Hospital, London W12 0HS, UK.
authors: Mona
authors: M
authors: El Bahrawy
authors: Department of Histopathology, Medical Research Institute, University of Dundee Medical School, Ninewells Hospital, Dundee DD1 9SY, UK.
authors: Stewart
authors: S
authors: Fleming
authors: Hypoxia Biology Laboratory, Henry Wellcome Building for Molecular Physiology, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Peter
authors: P
authors: Ratcliffe
authors: Department of Biomedicine, Research Group Human Genomics, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
authors: Karl
authors: K
authors: Heinimann
authors: 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.
authors: Charles
authors: C
authors: Swanton
authors: 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.
authors: Ian
authors: I
authors: Tomlinson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002874:Chromosome Mapping; D002875:Chromosomes / Q000648:ultrastructure*; D056915:DNA Copy Number Variations; D059472:Exome; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D000911:Antibodies, Monoclonal; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human