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Nat Genet. 2014 Mar;46(3):225-33. doi: 10.1038/ng.2891. Epub 2014 Feb 2.

Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing.

Author information

  • 11] Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK. [2].
  • 21] Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London, UK. [2].
  • 31] Department of Medicine, Royal Marsden Hospital, London, UK. [2].
  • 4Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
  • 5Department of Medicine, Royal Marsden Hospital, London, UK.
  • 6Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK.
  • 7Advanced Sequencing Facility, Cancer Research UK London Research Institute, London, UK.
  • 8Experimental Histopathology, Cancer Research UK London Research Institute, London, UK.
  • 9Biomolecular Modelling, Cancer Research UK London Research Institute, London, UK.
  • 10Department of Urology, Royal Marsden Hospital, London, UK.
  • 11Department of Pathology, Royal Marsden Hospital, London, UK.
  • 12Department of Genomic Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
  • 13Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London, UK.
  • 141] Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK. [2] University College London Cancer Institute, University College London, London, UK.

Abstract

Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73-75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development.

PMID:
24487277
[PubMed - indexed for MEDLINE]
PMCID:
PMC4636053
Free PMC Article
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