Somatic mutations affect key pathways in lung adenocarcinoma Journal Article


Authors: Ding, L.; Getz, G.; Wheeler, D. A.; Mardis, E. R.; McLellan, M. D.; Cibulskis, K.; Sougnez, C.; Greulich, H.; Muzny, D. M.; Morgan, M. B.; Fulton, L.; Fulton, R. S.; Zhang, Q.; Wendl, M. C.; Lawrence, M. S.; Larson, D. E.; Chen, K.; Dooling, D. J.; Sabo, A.; Hawes, A. C.; Shen, H.; Jhangiani, S. N.; Lewis, L. R.; Hall, O.; Zhu, Y.; Mathew, T.; Ren, Y.; Yao, J.; Scherer, S. E.; Clerc, K.; Metcalf, G. A.; Ng, B.; Milosavljevic, A.; Gonzalez-Garay, M. L.; Osborne, J. R.; Meyer, R.; Shi, X.; Tang, Y.; Koboldt, D. C.; Lin, L.; Abbott, R.; Miner, T. L.; Pohl, C.; Fewell, G.; Haipek, C.; Schmidt, H.; Dunford-Shore, B. H.; Kraja, A.; Crosby, S. D.; Sawyer, C. S.; Vickery, T.; Sander, S.; Robinson, J.; Winckler, W.; Baldwin, J.; Chirieac, L. R.; Dutt, A.; Fennell, T.; Hanna, M.; Johnson, B. E.; Onofrio, R. C.; Thomas, R. K.; Tonon, G.; Weir, B. A.; Zhao, X.; Ziaugra, L.; Zody, M. C.; Giordano, T.; Orringer, M. B.; Roth, J. A.; Spitz, M. R.; Wistuba, I. I.; Ozenberger, B.; Good, P. J.; Chang, A. C.; Beer, D. G.; Watson, M. A.; Ladanyi, M.; Broderick, S.; Yoshizawa, A.; Travis, W. D.; Pao, W.; Province, M. A.; Weinstock, G. M.; Varmus, H. E.; Gabriel, S. B.; Lander, E. S.; Gibbs, R. A.; Meyerson, M.; Wilson, R. K.
Article Title: Somatic mutations affect key pathways in lung adenocarcinoma
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. ©2008 Macmillan Publishers Limited. All rights reserved.
Keywords: single nucleotide polymorphism; somatic mutation; mutation; histopathology; gene targeting; gene expression; lung neoplasms; smoking; carcinogenesis; tumor suppressor gene; gene expression regulation, neoplastic; lung adenocarcinoma; dna; public health; dna sequence; gene dosage; tumor; genes, tumor suppressor; disease treatment; carcinogen; proto-oncogenes; adenocarcinoma, bronchiolo-alveolar; respiratory disease
Journal Title: Nature
Volume: 455
Issue: 7216
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2008-10-23
Start Page: 1069
End Page: 1075
Language: English
DOI: 10.1038/nature07423
PUBMED: 18948947
PROVIDER: scopus
PMCID: PMC2694412
DOI/URL:
Notes: --- - "Cited By (since 1996): 397" - "Export Date: 17 November 2011" - "CODEN: NATUA" - "Source: Scopus"
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MSK Authors
  1. William Pao
    141 Pao
  2. Marc Ladanyi
    1277 Ladanyi
  3. William D Travis
    712 Travis
  4. Harold Varmus
    96 Varmus