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Keywords:

  • cancer mutation;
  • receptor tyrosine kinase;
  • protein structure;
  • kinase activation;
  • mutation spectra;
  • double mutations

Abstract

Aberrant activation of receptor tyrosine kinases (RTKs) is a common feature of many cancer cells. It was previously suggested that the mechanisms of kinase activation in cancer might be linked to transitions between active and inactive states. Here, we estimate the effects of single and double cancer mutations on the stability of active and inactive states of the kinase domains from different RTKs. We show that singleton cancer mutations destabilize active and inactive states; however, inactive states are destabilized more than the active ones, leading to kinase activation. We show that there exists a relationship between the estimate of oncogenic potential of cancer mutation and kinase activation. Namely, more frequent mutations have a higher activating effect, which might allow us to predict the activating effect of the mutations from the mutation spectra. Independent evolutionary analysis of mutation spectra complements this observation and finds the same frequency threshold defining mutation hotspots. We analyze double mutations and report a positive epistasis and additional advantage of doublets with respect to cancer cell fitness. The activation mechanisms of double mutations differ from those of single mutations and double mutation spectrum is found to be dissimilar to the mutation spectrum of singletons. Hum Mutat 33:1566–1575, 2012. Published 2012 Wiley Periodicals, Inc.*