Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types

Sci Rep. 2017 Jul 25;7(1):6418. doi: 10.1038/s41598-017-06366-x.

Abstract

In this study we use somatic cancer mutations to identify important functional residues within sets of related genes. We focus on protein kinases, a superfamily of phosphotransferases that share homologous sequences and structural motifs and have many connections to cancer. We develop several statistical tests for identifying Significantly Mutated Positions (SMPs), which are positions in an alignment with mutations that show signs of selection. We apply our methods to 21,917 mutations that map to the alignment of human kinases and identify 23 SMPs. SMPs occur throughout the alignment, with many in the important A-loop region, and others spread between the N and C lobes of the kinase domain. Since mutations are pooled across the superfamily, these positions may be important to many protein kinases. We select eleven mutations from these positions for functional validation. All eleven mutations cause a reduction or loss of function in the affected kinase. The tested mutations are from four genes, including two tumor suppressors (TGFBR1 and CHEK2) and two oncogenes (KDR and ERBB2). They also represent multiple cancer types, and include both recurrent and non-recurrent events. Many of these mutations warrant further investigation as potential cancer drivers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Checkpoint Kinase 2 / genetics
  • Databases, Genetic
  • Humans
  • Loss of Function Mutation*
  • Mice
  • NIH 3T3 Cells
  • Neoplasms / enzymology
  • Neoplasms / genetics*
  • Phosphotransferases / chemistry
  • Phosphotransferases / genetics*
  • Phosphotransferases / metabolism
  • Receptor, ErbB-2 / genetics
  • Receptor, Transforming Growth Factor-beta Type I / genetics
  • Reproducibility of Results
  • Vascular Endothelial Growth Factor Receptor-2 / genetics

Substances

  • Phosphotransferases
  • Checkpoint Kinase 2
  • ERBB2 protein, human
  • KDR protein, human
  • Receptor, ErbB-2
  • Vascular Endothelial Growth Factor Receptor-2
  • CHEK2 protein, human
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human