Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Nature. 2010 Aug 12;466(7308):869-73. doi: 10.1038/nature09208. Epub 2010 Jul 28.
The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics. Here we report the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for galpha subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Galpha subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.
系统地描述癌症基因组中的体细胞突变对于理解疾病和开发靶向治疗至关重要。在这里，我们报告了在代表来自 441 个肿瘤的 1507 个编码基因的大约 1800 兆碱基的 DNA 中鉴定出 2576 个体细胞突变。我们发现，突变率和突变基因的集合在肿瘤类型和亚型之间有很大的差异。统计分析确定了 77 个明显突变的基因，包括蛋白激酶、G 蛋白偶联受体，如 GRM8、BAI3、AGTRL1（也称为 APLNR）和 LPHN3，以及其他可用药的靶点。体细胞突变和拷贝数改变的综合分析确定了另外 35 个明显改变的基因，包括 GNAS，表明 Galpha 亚基在多种癌症中的作用扩大。此外，我们的实验分析证明了突变 GNAO1（Galpha 亚基）和突变 MAP2K4（JNK 信号通路的一个成员）在肿瘤发生中的功能作用。我们的研究提供了主要人类癌症突变谱的概述，并确定了几个潜在的治疗靶点。
