Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles.
Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles.
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DOI：
10.1158/2159-8290.cd-16-0160
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发表时间：
2016-07
期刊：
影响因子：
28.2
通讯作者：
Hahn WC
中科院分区：
文献类型：
--
作者：
Kim E;Ilic N;Shrestha Y;Zou L;Kamburov A;Zhu C;Yang X;Lubonja R;Tran N;Nguyen C;Lawrence MS;Piccioni F;Bagul M;Doench JG;Chouinard CR;Wu X;Hogstrom L;Natoli T;Tamayo P;Horn H;Corsello SM;Lage K;Root DE;Subramanian A;Golub TR;Getz G;Boehm JS;Hahn WC
癌症基因组表征工作现在提供了对原发肿瘤的体细胞变化的初步看法。然而，大多数点突变发生的频率很低。这些等位基因的功能仍未确定。我们已经开发了一种可扩展的系统方法来询问癌症相关基因变体的功能。我们对来自5,338个肿瘤的474个突变等位基因进行体内混合肿瘤形成分析和基因表达谱分析。我们鉴定了12个转化等位基因，其中包括两个未被证实致癌的In基因(PIK3CB、POT1)。一种罕见的KRAS等位基因D33E显示出已知的RAS效应通路的致瘤性和结构性激活。通过比较野生型和突变型等位基因表达诱导的基因表达变化，推测特定等位基因的活性。由于在5338个使细胞发生肿瘤的肿瘤中只发现一种等位基因发生突变，这些观察结果强调了将基因组信息与功能研究相结合的价值。
Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency. and the function of these alleles remain undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic. One rare KRAS allele, D33E, displayed tumorigenicity and constitutive activation of known RAS effector pathways. By comparing gene expression changes induced upon expression of wild type and mutant alleles, we inferred the activity of specific alleles. Since alleles found to be mutated only once in 5,338 tumors rendered cells tumorigenic, these observations underscore the value of integrating genomic information with functional studies.