Systematic Analysis of Somatic Mutations in Phosphorylation Signaling Predicts Novel Cancer Drivers

Mol Syst Biol. 2013;9:637. doi: 10.1038/msb.2012.68.

Abstract

Large-scale cancer genome sequencing has uncovered thousands of gene mutations, but distinguishing tumor driver genes from functionally neutral passenger mutations is a major challenge. We analyzed 800 cancer genomes of eight types to find single-nucleotide variants (SNVs) that precisely target phosphorylation machinery, important in cancer development and drug targeting. Assuming that cancer-related biological systems involve unexpectedly frequent mutations, we used novel algorithms to identify genes with significant phosphorylation-associated SNVs (pSNVs), phospho-mutated pathways, kinase networks, drug targets, and clinically correlated signaling modules. We highlight increased survival of patients with TP53 pSNVs, hierarchically organized cancer kinase modules, a novel pSNV in EGFR, and an immune-related network of pSNVs that correlates with prolonged survival in ovarian cancer. Our findings include multiple actionable cancer gene candidates (FLNB, GRM1, POU2F1), protein complexes (HCF1, ASF1), and kinases (PRKCZ). This study demonstrates new ways of interpreting cancer genomes and presents new leads for cancer research.

Publication types

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

MeSH terms

  • Algorithms*
  • Contractile Proteins / genetics
  • Contractile Proteins / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Filamins
  • Genes, p53
  • Glioblastoma / genetics
  • Humans
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Models, Statistical
  • Mutation*
  • Neoplasms / genetics*
  • Neoplasms / mortality*
  • Octamer Transcription Factor-1 / genetics
  • Octamer Transcription Factor-1 / metabolism
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / mortality
  • Phosphorylation*
  • Polymorphism, Single Nucleotide
  • Predictive Value of Tests
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Proteins / genetics*
  • Proteins / metabolism*
  • Signal Transduction / genetics

Substances

  • Contractile Proteins
  • FLNB protein, human
  • Filamins
  • Microfilament Proteins
  • Octamer Transcription Factor-1
  • POU2F1 protein, human
  • Proteins
  • Protein Kinases
  • EGFR protein, human
  • ErbB Receptors
  • protein kinase C zeta
  • Protein Kinase C