title: Somatic mutations of the protein kinase gene family in human lung cancer.
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.
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, United Kingdom.
authors.forename: Helen
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authors.lastname: Davies
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authors.lastname: Brackenbury
authors.forename: Gemma
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authors.lastname: Solomon
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authors.lastname: Stephens
authors.forename: Calli
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authors.lastname: Tofts
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authors.lastname: Varian
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authors.lastname: Webb
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authors.lastname: West
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authors.lastname: Widaa
authors.forename: Andrew
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authors.lastname: Yates
authors.forename: Francis
authors.initials: F
authors.lastname: Brasseur
authors.forename: Colin S
authors.initials: CS
authors.lastname: Cooper
authors.forename: Adrienne M
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authors.lastname: Flanagan
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authors.initials: A
authors.lastname: Green
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authors.lastname: Knowles
authors.forename: Suet Y
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authors.lastname: Leung
authors.forename: Leendert H J
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authors.lastname: Looijenga
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authors.lastname: Malkowicz
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authors.lastname: Pierotti
authors.forename: Bin T
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authors.lastname: Teh
authors.forename: Siu T
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authors.lastname: Yuen
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Weber
authors.forename: Peter
authors.initials: P
authors.lastname: Goldstraw
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
authors.forename: Richard
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authors.lastname: Wooster
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mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics; D002276:Carcinoid Tumor / Q000201:enzymology / Q000235:genetics; D018287:Carcinoma, Large Cell / Q000201:enzymology / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics*
chemical_list: D011494:Protein Kinases