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
The Genome Center at Washington University, Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Nature. 2008 Oct 23;455(7216):1069-75. doi: 10.1038/nature07423.
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.
确定癌症的遗传基础需要对大量组织病理学分类良好的原发性肿瘤进行全面分析。在此，我们报告一项合作研究的结果，该研究旨在发现188例人类肺腺癌中的体细胞突变。对623个与癌症有已知或潜在关系的基因进行DNA测序，在样本中发现了1000多个体细胞突变。我们的分析确定了26个突变频率显著较高的基因，因此它们可能参与了致癌过程。频繁突变的基因包括酪氨酸激酶，其中有EGFR同源物ERBB4；多个 Ephrin 受体基因，特别是EPHA3；血管内皮生长因子受体KDR；以及NTRK基因。这些数据为几种在其他癌症中涉及的肿瘤抑制基因——包括NF1、APC、RB1和ATM——在原发性肺腺癌中的体细胞突变，以及PTPRD的序列变化和经常缺失的基因LRP1B提供了证据。观察到的突变谱与临床特征、吸烟状况和DNA修复缺陷相关。包括单核苷酸多态性阵列和基因表达阵列在内的数据整合进一步证实了这些结果。我们的发现进一步揭示了肺腺癌中涉及的几个重要信号通路，并提出了新的治疗分子靶点。
