Exome Sequencing Identifies Recurrent Somatic RAC1 Mutations in Melanoma

Nat Genet. 2012 Sep;44(9):1006-14. doi: 10.1038/ng.2359. Epub 2012 Jul 29.

Abstract

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • DNA Mutational Analysis
  • Exome / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Melanoma / epidemiology
  • Melanoma / genetics*
  • Middle Aged
  • Models, Molecular
  • Mutation* / physiology
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Sequence Analysis, DNA
  • Skin Neoplasms / epidemiology
  • Skin Neoplasms / genetics*
  • Uveal Neoplasms / epidemiology
  • Uveal Neoplasms / genetics
  • rac1 GTP-Binding Protein / chemistry
  • rac1 GTP-Binding Protein / genetics*

Substances

  • RAC1 protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • rac1 GTP-Binding Protein

Supplementary concepts

  • Uveal melanoma

Associated data

  • PDB/3SBD
  • PDB/3SBE
  • PDB/3TH5