Somatic mutations affect key pathways in lung adenocarcinoma

Li Ding, Gad Getz, David A. Wheeler, Elaine R. Mardis, Michael D. McLellan, Kristian Cibulskis, Carrie Sougnez, Heidi Greulich, Donna M. Muzny, Margaret B. Morgan, Lucinda Fulton, Robert S. Fulton, Qunyuan Zhang, Michael C. Wendl, Michael S. Lawrence, David E. Larson, Ken Chen, David J. Dooling, Aniko Sabo, Alicia C. HawesHua Shen, Shalini N. Jhangiani, Lora R. Lewis, Otis Hall, Yiming Zhu, Tittu Mathew, Yanru Ren, Jiqiang Yao, Steven E. Scherer, Kerstin Clerc, Ginger A. Metcalf, Brian Ng, Aleksandar Milosavljevic, Manuel L. Gonzalez-Garay, John R. Osborne, Rick Meyer, Xiaoqi Shi, Yuzhu Tang, Daniel C. Koboldt, Ling Lin, Rachel Abbott, Tracie L. Miner, Craig Pohl, Ginger Fewell, Carrie Haipek, Heather Schmidt, Brian H. Dunford-Shore, Aldi Kraja, Seth D. Crosby, Christopher S. Sawyer, Tammi Vickery, Sacha Sander, Jody Robinson, Wendy Winckler, Jennifer Baldwin, Lucian R. Chirieac, Amit Dutt, Tim Fennell, Megan Hanna, Bruce E. Johnson, Robert C. Onofrio, Roman K. Thomas, Giovanni Tonon, Barbara A. Weir, Xiaojun Zhao, Liuda Ziaugra, Michael C. Zody, Thomas Giordano, Mark B. Orringer, Jack A. Roth, Margaret R. Spitz, Ignacio I. Wistuba, Bradley Ozenberger, Peter J. Good, Andrew C. Chang, David G. Beer, Mark A. Watson, Marc Ladanyi, Stephen Broderick, Akihiko Yoshizawa, William D. Travis, William Pao, Michael A. Province, George M. Weinstock, Harold E. Varmus, Stacey B. Gabriel, Eric S. Lander, Richard A. Gibbs, Matthew Meyerson, Richard K. Wilson

Research output: Contribution to journalArticlepeer-review

2271 Scopus citations


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.

Original languageEnglish
Pages (from-to)1069-1075
Number of pages7
Issue number7216
StatePublished - Oct 23 2008


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