Somatic mutations affect key pathways in lung adenocarcinoma by Ding Li, Getz Gad, Wheeler David A, Mardis Elaine R, McLellan Michael D, Cibulskis Kristian, Sougnez Carrie, Greulich Heidi, Muzny Donna M, Morgan Margaret B, Fulton Lucinda, Fulton Robert S, Zhang Qunyuan, Wendl Michael C, Lawrence Michael S, Larson David E, Chen Ken, Dooling David J, Sabo Aniko, Hawes Alicia C, Shen Hua, Jhangiani Shalini N, Lewis Lora R, Hall Otis, Zhu Yiming, Mathew Tittu, Ren Yanru, Yao Jiqiang, Scherer Steven E, Clerc Kerstin, Metcalf Ginger A, Ng Brian, Milosavljevic Aleksandar, Gonzalez-Garay Manuel L, Osborne John R, Meyer Rick, Shi Xiaoqi, Tang Yuzhu, Koboldt Daniel C, Lin Ling, Abbott Rachel, Miner Tracie L, Pohl Craig, Fewell Ginger, Haipek Carrie, Schmidt Heather, Dunford-Shore Brian H, Kraja Aldi, Crosby Seth D, Sawyer Christopher S, Vickery Tammi, Sander Sacha, Robinson Jody, Winckler Wendy, Baldwin Jennifer, Chirieac Lucian R, Dutt Amit, Fennell Tim, Hanna Megan, Johnson Bruce E, Onofrio Robert C, Thomas Roman K, Tonon Giovanni, Weir Barbara A, Zhao Xiaojun, Ziaugra Liuda, Zody Michael C, Giordano Thomas, Orringer Mark B, Roth Jack A, Spitz Margaret R, Wistuba Ignacio I, Ozenberger Bradley, Good Peter J, Chang Andrew C, Beer David G, Watson Mark A, Ladanyi Marc, Broderick Stephen, Yoshizawa Akihiko, Travis William D, Pao William, Province Michael A, Weinstock George M, Varmus Harold E, Gabriel Stacey B, Lander Eric S, Gibbs Richard A, Meyerson Matthew, Wilson Richard K in Nature (2008). PubMed

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.

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