Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer.
Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer.
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DOI：
10.1158/2159-8290.cd-16-1045
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发表时间：
2017-04
期刊：
影响因子：
28.2
通讯作者：
Ideker T
中科院分区：
文献类型：
--
作者：
Carter H;Marty R;Hofree M;Gross AM;Jensen J;Fisch KM;Wu X;DeBoever C;Van Nostrand EL;Song Y;Wheeler E;Kreisberg JF;Lippman SM;Yeo GW;Gutkind JS;Ideker T
最近的研究已经描述了癌症期间出现的广泛的体细胞改变。然而，肿瘤的体细胞进化可能受到种系中携带的遗传多态性的显著影响。在这里，我们分析了5954个肿瘤的基因组数据，以揭示和系统地验证生殖系多态性和主要体细胞事件之间的412种遗传相互作用，包括特定组织中的肿瘤形成和特定癌症基因的改变。在生殖细胞-体细胞相互作用中，我们发现RBFOX 1的生殖细胞变体通过RNA剪接的功能改变使SF 3B 1体细胞突变的发生率增加了8倍。类似地，19p13.3变体与PTEN体细胞突变的可能性增加四倍相关。为了支持这种关联，我们发现PTEN敲低使MTOR通路对19p13.3基因GNA 11的高表达敏感。最后，我们观察到，通过生殖系多态性对患者进行分层暴露了不同的体细胞突变景观，涉及新的癌症基因。这项研究创建了一个经过验证的遗传变异资源，这些变异控制着癌症在哪里以及如何发展，为预防研究开辟了途径。
Recent studies have characterized the extensive somatic alterations that arise during cancer. However, the somatic evolution of a tumor may be significantly affected by inherited polymorphisms carried in the germline. Here, we analyze genomic data for 5954 tumors to reveal and systematically validate 412 genetic interactions between germline polymorphisms and major somatic events, including tumor formation in specific tissues and alteration of specific cancer genes. Among germline-somatic interactions, we find germline variants in RBFOX1 that increase incidence of SF3B1 somatic mutation by eight-fold via functional alterations in RNA splicing. Similarly, 19p13.3 variants are associated with a four-fold increased likelihood of somatic mutations in PTEN. In support of this association, we find that PTEN knock-down sensitizes the MTOR pathway to high expression of the 19p13.3 gene GNA11. Finally, we observe that stratifying patients by germline polymorphisms exposes distinct somatic mutation landscapes, implicating new cancer genes. This study creates a validated resource of inherited variants that govern where and how cancer develops, opening avenues for prevention research.