Somatic mutations of the protein kinase gene family in human lung cancer

Helen Davies, Chris Hunter, Raffaella Smith, Philip Stephens, Christopher Greenman, Graham Bignell, Jon Teague, Adam Butler, Sarah Edkins, Claire Stevens, Adrian Parker, Sarah O'Meara, Tim Avis, Syd Barthorpe, Lisa Brackenbury, Gemma Buck, Jody Clements, Jennifer Cole, Ed Dicks, Ken EdwardsSimon Forbes, Matthew Gorton, Kristian Gray, Kelly Halliday, Rachel Harrison, Katy Hills, Jonathon Hinton, David Jones, Vivienne Kosmidou, Ross Laman, Richard Lugg, Andrew Menzies, Janet Perry, Robert Petty, Keiran Raine, Rebecca Shepherd, Alexandra Small, Helen Solomon, Yvonne Stephens, Calli Tofts, Jennifer Varian, Anthony Webb, Sofie West, Sara Widaa, Andrew Yates, Francis Brasseur, Colin S Cooper, Adrienne M Flanagan, Anthony Green, Maggie Knowles, Suet Y Leung, Leendert H J Looijenga, Bruce Malkowicz, Marco A Pierotti, Bin T Teh, Siu T Yuen, Sunil R Lakhani, Douglas F Easton, Barbara L Weber, Peter Goldstraw, Andrew G Nicholson, Richard Wooster, Michael R Stratton, P Andrew Futreal

Research output: Contribution to journalArticlepeer-review

385 Citations (Scopus)

Abstract

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.
Original languageEnglish
Pages (from-to)7591-5
Number of pages5
JournalCancer Research
Volume65
Issue number17
DOIs
Publication statusPublished - 1 Sep 2005

Keywords

  • Adenocarcinoma
  • Carcinoid Tumor
  • Carcinoma, Large Cell
  • Carcinoma, Squamous Cell
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Humans
  • Lung Neoplasms
  • Mutation
  • Protein Kinases

Cite this