Genomic Architecture and Evolution of Clear Cell Renal Cell Carcinomas Defined by Multiregion Sequencing

Nat Genet. 2014 Mar;46(3):225-233. doi: 10.1038/ng.2891. Epub 2014 Feb 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Renal Cell / genetics*
  • Class I Phosphatidylinositol 3-Kinases
  • CpG Islands
  • DNA Copy Number Variations
  • Disease Progression
  • Evolution, Molecular
  • Exome
  • Genomics
  • High-Throughput Nucleotide Sequencing
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Kidney Neoplasms / genetics*
  • Mutation*
  • Nuclear Proteins / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Phylogeny
  • Polymorphism, Single Nucleotide
  • Transcription Factors / genetics
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics

Substances

  • BAP1 protein, human
  • Nuclear Proteins
  • PBRM1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Histone-Lysine N-Methyltransferase
  • Set2 protein, human
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Ubiquitin Thiolesterase
  • VHL protein, human

Associated data

  • GEO/GSE53000