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

Research output: Contribution to journalArticlepeer-review

Authors

  • Michal B. Kovac
  • Carolina Navas
  • Stuart Horswell
  • Max Salm
  • 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 M. Terracciano
  • Serenella Eppenberger-Castori
  • Andrew Protheroe
  • Eamonn Maher
  • Mona A. El Bahrawy
  • Stewart Fleming
  • Peter Ratcliffe
  • Karl Heinimann
  • Charles Swanton

Colleges, School and Institutes

External organisations

  • Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics
  • Department of Biomedicine, Research Group Human Genomics, University of Basel
  • Translational Cancer Therapeutics Laboratory, London Research Institute, Cancer Research UK
  • Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK
  • UCL Cancer Institute
  • Faculty of Mechanical Engineering, Institute of Mathematics and Physics, Slovak University of Technology
  • Department of Medicine, The Royal Marsden NHS Foundation Trust
  • Department of Urology, The Royal Marsden NHS Foundation Trust
  • School of Medicine, The University of Queensland
  • Department of Histopathology, The Royal Marsden NHS Foundation Trust
  • Experimental Histopathology, London Research Institute, Cancer Research UK
  • Urology Centre, Guy's and St Thomas's Hospital NHS Foundation Trust
  • Advanced Sequencing Laboratory, London Research Institute, Cancer Research UK
  • Genomic analysis of tumour development, Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria
  • Department of Histopathology, Guy's and St Thomas's Hospital NHS Foundation Trust
  • Department of Oncology, Uro-Oncology Research Group, University of Cambridge
  • University Hospitals Birmingham NHS Foundation Trust
  • Institute for Pathology, University Hospital Basel
  • University of Cambridge
  • Imperial College London
  • University of Dundee
  • 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.

Details

Original languageEnglish
Article number6336
JournalNature Communications
Volume6
Publication statusPublished - 19 Mar 2015

Keywords

  • Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal/chemistry, Carcinoma, Renal Cell/genetics, Chromosome Mapping, Chromosomes/ultrastructure, DNA Copy Number Variations, Exome, Exons, Female, Gene Expression Regulation, Neoplastic, Histone-Lysine N-Methyltransferase/genetics, Humans, Kidney Neoplasms/genetics, Loss of Heterozygosity, Male, Middle Aged, Mutation, Phylogeny, Polymorphism, Single Nucleotide, Sequence Analysis, DNA