3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets

Genome Med. 2017 Jan 23;9(1):4. doi: 10.1186/s13073-016-0393-x.

Abstract

Many mutations in cancer are of unknown functional significance. Standard methods use statistically significant recurrence of mutations in tumor samples as an indicator of functional impact. We extend such analyses into the long tail of rare mutations by considering recurrence of mutations in clusters of spatially close residues in protein structures. Analyzing 10,000 tumor exomes, we identify more than 3000 rarely mutated residues in proteins as potentially functional and experimentally validate several in RAC1 and MAP2K1. These potential driver mutations (web resources: 3dhotspots.org and cBioPortal.org) can extend the scope of genomically informed clinical trials and of personalized choice of therapy.

Keywords: Cancer genomics; Driver mutations; Precision medicine; Protein structures.

Publication types

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

MeSH terms

  • DNA Mutational Analysis / methods*
  • Exome
  • Genomics / methods*
  • Humans
  • MAP Kinase Kinase 1 / chemistry
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • Mutation*
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Protein Structure, Tertiary
  • rac1 GTP-Binding Protein / chemistry
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Neoplasm Proteins
  • RAC1 protein, human
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • rac1 GTP-Binding Protein