A Landscape of Driver Mutations in Melanoma

Cell. 2012 Jul 20;150(2):251-63. doi: 10.1016/j.cell.2012.06.024.

Abstract

Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which-RAC1, PPP6C, and STK19-harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cells, Cultured
  • Exome
  • Genome-Wide Association Study*
  • Humans
  • Melanocytes / metabolism
  • Melanoma / genetics*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis*
  • Proto-Oncogene Proteins B-raf / genetics
  • Sequence Alignment
  • Ultraviolet Rays*
  • rac1 GTP-Binding Protein / genetics

Substances

  • RAC1 protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • rac1 GTP-Binding Protein