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1 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus; 2 Cancer Research UK Genetic Epidemiology Group, Strangeways Research Laboratories; 3 Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom; 4 Ludwig Institute for Cancer Research, Brussels, Belgium; 5 Institute of Cancer Research, Sutton, Surrey, United Kingdom; 6 Royal Free and University College Medical School and 7 Royal Brompton Hospital, London, United Kingdom; 8 Cancer Research UK Clinical Centre, St. James University Hospital, Leeds, United Kingdom; 9 Department of Pathology, The University of Hong Kong, Hong Kong; 10 Josephine Nefkens Institute, Erasmus University, Rotterdam, GE Rotterdam, the Netherlands; 11 Division of Urology, University of Pennsylvania; 12 University of Pennsylvania Cancer Centre, Philadelphia, Pennsylvania; 13 Instituto Nazionale Tumori and FIRC Department of Experimental Oncology, Institute of Molecular Oncology, Milan, Italy; and 14 Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan
Requests for reprints: Richard Wooster, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, United Kingdom. Phone: 44-1223-834244; Fax: 44-1223-494809; E-mail: rw1{at}sanger.ac.uk.
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 (
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 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.
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