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Nature DOI:10.1038/nature07423

Somatic mutations affect key pathways in lung adenocarcinoma.

Publication TypeJournal Article
Year of Publication2008
AuthorsDing, L, Getz, G, Wheeler, DA, Mardis, ER, McLellan, MD, Cibulskis, K, Sougnez, C, Greulich, H, Muzny, DM, Morgan, MB, Fulton, L, Fulton, RS, Zhang, Q, Wendl, MC, Lawrence, MS, Larson, DE, Chen, K, Dooling, DJ, Sabo, A, Hawes, AC, Shen, H, Jhangiani, SN, Lewis, LR, Hall, O, Zhu, Y, Mathew, T, Ren, Y, Yao, J, Scherer, SE, Clerc, K, Metcalf, GA, Ng, B, Milosavljevic, A, Gonzalez-Garay, ML, Osborne, JR, Meyer, R, Shi, X, Tang, Y, Koboldt, DC, Lin, L, Abbott, R, Miner, TL, Pohl, C, Fewell, G, Haipek, C, Schmidt, H, Dunford-Shore, BH, Kraja, A, Crosby, SD, Sawyer, CS, Vickery, T, Sander, S, Robinson, J, Winckler, W, Baldwin, J, Chirieac, LR, Dutt, A, Fennell, T, Hanna, M, Johnson, BE, Onofrio, RC, Thomas, RK, Tonon, G, Weir, BA, Zhao, X, Ziaugra, L, Zody, MC, Giordano, T, Orringer, MB, Roth, JA, Spitz, MR, Wistuba, II, Ozenberger, B, Good, PJ, Chang, AC, Beer, DG, Watson, MA, Ladanyi, M, Broderick, S, Yoshizawa, A, Travis, WD, Pao, W, Province, MA, Weinstock, GM, Varmus, HE, Gabriel, SB, Lander, ES, Gibbs, RA, Meyerson, M, Wilson, RK
JournalNature
Volume455
Issue7216
Pages1069-75
Date Published2008 Oct 23
ISSN1476-4687
KeywordsAdenocarcinoma, Bronchiolo-Alveolar, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Humans, Lung Neoplasms, Male, Mutation, Proto-Oncogenes
Abstract

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.

URLhttp://dx.doi.org/10.1038/nature07423
DOI10.1038/nature07423
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/18948947?dopt=Abstract

Alternate JournalNature
PubMed ID18948947
PubMed Central IDPMC2694412
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
U19 CA084953-050003 / CA / NCI NIH HHS / United States
U54 HG003067-04 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
P50 CA070907 / CA / NCI NIH HHS / United States
U19 CA084953 / CA / NCI NIH HHS / United States
R01 CA154365 / CA / NCI NIH HHS / United States