Somatic Mutations of the Protein Kinase Gene Family in Human Lung Cancer

作者：Helen Ruth Davies, Chris Hunter, Raffaella Smith, Philip Stephens, Chris Greenman, Graham R. Bignell, Jon W. Teague, Adam P. Butler, Sarah Edkins, Claire Stevens, Adrian G. Parker, Sarah O’Meara, Tim Avis, Syd Barthorpe, Lisa Brackenbury, Gemma Buck, Jody Clements, Jennifer M. Cole, Ed Dicks, Ken Edwards, Simon Andrew Forbes, Matthew Gorton, Kristian A. Gray, Kelly Halliday, Rachel Harrison, Katy Hills, Jonathon Hinton, David Jones, Vivienne Kosmidou, Ross Laman, Richard Lugg, Andrew H. Menzies, Janet Perry, Robert D. Petty, Keiran M. Raine, Rebecca F. Shepherd, Alexandra C. Small, Helen Solomon, Yvonne Stephens, Calli Tofts, Jennifer Varian, Anthony Webb, Sofie West, Sara Widaa, Andrew D. Yates, Francis Brasseur, Colin S. Cooper, Adrienne Margaret Flanagan, Anthony Richard Green, Maggie Knowles, Suet Yi Leung, Leendert H. J. Looijenga, Bruce S. Malkowicz, Marco Alessandro Pierotti, Bin Tean Teh, Siu Tsan Yuen, Sunil R. Lakhani, Douglas F. Easton, Barbara L. Weber, Peter Goldstraw, Andrew Gordon Nicholson, Richard Wooster, Michael R. Stratton, P. Andrew Futreal · 发表于：Cancer Research · 年份：2005 · DOI：10.1158/0008-5472.can-05-1855 · 被引用次数：468 · 研究领域：Cancer Genomics and Diagnostics、Lung Cancer Treatments and Mutations、BRCA gene mutations in cancer

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.