Characterizing genomic alterations in cancer by complementary functional associations.
Characterizing genomic alterations in cancer by complementary functional associations.
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DOI：
10.1038/nbt.3527
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发表时间：
2016-05
影响因子：
46.9
通讯作者：
Tamayo P
中科院分区：
文献类型：
--
作者：
Kim JW;Botvinnik OB;Abudayyeh O;Birger C;Rosenbluh J;Shrestha Y;Abazeed ME;Hammerman PS;DiCara D;Konieczkowski DJ;Johannessen CM;Liberzon A;Alizad-Rahvar AR;Alexe G;Aguirre A;Ghandi M;Greulich H;Vazquez F;Weir BA;Van Allen EM;Tsherniak A;Shao DD;Zack TI;Noble M;Getz G;Beroukhim R;Garraway LA;Ardakani M;Romualdi C;Sales G;Barbie DA;Boehm JS;Hahn WC;Mesirov JP;Tamayo P
对癌症基因组测序的系统性努力已经确定了人类癌症中大量的相关突变和拷贝数改变;然而，阐明它们的功能后果以及它们驱动或维持致癌状态的相互作用仍然是一个重大挑战。在这里，我们介绍了REVEALER，一种计算方法，识别与功能表型相关的互斥基因组改变的组合，如致癌途径的激活或基因依赖性或对药物治疗的敏感性。我们使用REVEALER来揭示与β-catenin和NRF 2的转录激活、MEK抑制剂敏感性和KRAS依赖性相关的互补基因组改变。REVEALER成功地鉴定了已知和新的关联，证明了将功能谱与癌症基因组中基因组改变的广泛表征相结合的能力。
Systematic efforts to sequence the cancer genome have identified large numbers of relevant mutations and copy number alterations in human cancers; however, elucidating their functional consequences, and their interactions to drive or maintain oncogenic states, is still a significant challenge. Here we introduce REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene-dependency of oncogenic pathways or the sensitivity to a drug treatment. We use REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes.