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Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

Gillian L Dalgliesh1, Kyle Furge, Chris Greenman

  • 1Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

Nature
|January 8, 2010
PubMed

Insights

Researchers identified new genetic mutations in clear cell renal cell carcinoma (ccRCC), a common kidney cancer. These mutations affect genes involved in histone modification, revealing significant genetic diversity beyond VHL gene mutations.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Clear cell renal cell carcinoma (ccRCC) is the most prevalent adult kidney cancer.
  • Most ccRCC cases feature inactivating mutations in the VHL gene.
  • Somatic mutations in known cancer genes are infrequent in ccRCC.

Purpose of the Study:

  • To further elucidate the genetic landscape of ccRCC.
  • To identify novel genes and pathways implicated in ccRCC development.

Main Methods:

  • Sequencing of 101 ccRCC cases across 3,544 protein-coding genes.
  • Identification and analysis of somatic mutations.

Main Results:

  • Discovered inactivating mutations in SETD2 (histone H3 lysine 36 methyltransferase) and JARID1C/KDM5C (histone H3 lysine 4 demethylase).
  • Confirmed mutations in UTX/KMD6A (histone H3 lysine 27 demethylase).
  • Identified NF2 mutations in ccRCC cases without VHL mutations and other potential cancer genes.

Conclusions:

  • Mutations in chromatin modification machinery components play a role in ccRCC pathogenesis.
  • Significant genetic heterogeneity exists in ccRCC, extending beyond VHL gene mutations.
  • Systematic genetic screens are crucial for a comprehensive understanding of ccRCC's somatic genetic architecture.

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