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SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair.
Kanu, N; Grönroos, E; Martinez, P; Burrell, R A; Yi Goh, X; Bartkova, J; Maya-Mendoza, A; Mistrík, M; Rowan, A J; Patel, H; Rabinowitz, A; East, P; Wilson, G; Santos, C R; McGranahan, N; Gulati, S; Gerlinger, M; Birkbak, N J; Joshi, T; Alexandrov, L B; Stratton, M R; Powles, T; Matthews, N; Bates, P A; Stewart, A; Szallasi, Z; Larkin, J; Bartek, J; Swanton, C.
Afiliación
  • Kanu N; UCL Cancer Institute, Paul O'Gorman Building, London, UK.
  • Grönroos E; Cancer Research UK London Research Institute, London, UK.
  • Martinez P; Cancer Research UK London Research Institute, London, UK.
  • Burrell RA; Cancer Research UK London Research Institute, London, UK.
  • Yi Goh X; Cancer Research UK London Research Institute, London, UK.
  • Bartkova J; Danish Cancer Society Research Center, Copenhagen, Denmark.
  • Maya-Mendoza A; Danish Cancer Society Research Center, Copenhagen, Denmark.
  • Mistrík M; Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University, Olomouc, Czech Republic.
  • Rowan AJ; Cancer Research UK London Research Institute, London, UK.
  • Patel H; Cancer Research UK London Research Institute, London, UK.
  • Rabinowitz A; Cancer Research UK London Research Institute, London, UK.
  • East P; Cancer Research UK London Research Institute, London, UK.
  • Wilson G; Cancer Research UK London Research Institute, London, UK.
  • Santos CR; Cancer Research UK London Research Institute, London, UK.
  • McGranahan N; Cancer Research UK London Research Institute, London, UK.
  • Gulati S; Cancer Research UK London Research Institute, London, UK.
  • Gerlinger M; Cancer Research UK London Research Institute, London, UK.
  • Birkbak NJ; UCL Cancer Institute, Paul O'Gorman Building, London, UK.
  • Joshi T; Cancer Research UK London Research Institute, London, UK.
  • Alexandrov LB; Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
  • Stratton MR; Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
  • Powles T; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridgeshire, UK.
  • Matthews N; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridgeshire, UK.
  • Bates PA; Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, London, UK.
  • Stewart A; Cancer Research UK London Research Institute, London, UK.
  • Szallasi Z; Cancer Research UK London Research Institute, London, UK.
  • Larkin J; Cancer Research UK London Research Institute, London, UK.
  • Bartek J; Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
  • Swanton C; Children's Hospital Boston, Informatics-Enders 1506, Boston, MA, USA.
Oncogene ; 34(46): 5699-708, 2015 Nov 12.
Article en En | MEDLINE | ID: mdl-25728682
Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / N-Metiltransferasa de Histona-Lisina / Neoplasias Renales / Mutación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2015 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / N-Metiltransferasa de Histona-Lisina / Neoplasias Renales / Mutación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2015 Tipo del documento: Article Pais de publicación: Reino Unido