Melanoma Genome Sequencing Reveals Frequent PREX2 Mutations

Nature. 2012 May 9;485(7399):502-6. doi: 10.1038/nature11071.

Abstract

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.

Publication types

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

MeSH terms

  • Chromosome Breakpoints / radiation effects
  • DNA Damage
  • DNA Mutational Analysis
  • Gene Expression Regulation, Neoplastic
  • Genome, Human / genetics*
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Melanocytes / metabolism
  • Melanocytes / pathology
  • Melanoma / genetics*
  • Melanoma / pathology
  • Mutagenesis / radiation effects
  • Mutation / genetics*
  • Mutation / radiation effects
  • Oncogenes / genetics
  • Sunlight / adverse effects*
  • Ultraviolet Rays / adverse effects

Substances

  • Guanine Nucleotide Exchange Factors
  • PREX2 protein, human