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Molecular Signatures of Fusion Proteins in Cancer
ACS Pharmacology & Translational Science Pub Date : 2019-03-27 , DOI: 10.1021/acsptsci.9b00019
Natasha S Latysheva 1 , M Madan Babu 1
Affiliation  

Although gene fusions are recognized as driver mutations in a wide variety of cancers, the general molecular mechanisms underlying oncogenic fusion proteins are insufficiently understood. Here, we employ large-scale data integration and machine learning and (1) identify three functionally distinct subgroups of gene fusions and their molecular signatures; (2) characterize the cellular pathways rewired by fusion events across different cancers; and (3) analyze the relative importance of over 100 structural, functional, and regulatory features of ∼2200 gene fusions. We report subgroups of fusions that likely act as driver mutations and find that gene fusions disproportionately affect pathways regulating cellular shape and movement. Although fusion proteins are similar across different cancer types, they affect cancer type-specific pathways. Key indicators of fusion-forming proteins include high and nontissue specific expression, numerous splice sites, and higher centrality in protein-interaction networks. Together, these findings provide unifying and cancer type-specific trends across diverse oncogenic fusion proteins.

中文翻译:

融合蛋白在癌症中的分子特征

尽管基因融合被认为是多种癌症中的驱动突变,但人们对致癌融合蛋白的一般分子机制仍知之甚少。在这里,我们采用大规模数据集成和机器学习,并且(1)确定三个功能不同的基因融合亚组及其分子特征;(2) 表征由不同癌症的融合事件重新连接的细胞通路;(3) 分析 2200 多个基因融合的 100 多个结构、功能和调控特征的相对重要性。我们报告了可能作为驱动突变的融合亚组,并发现基因融合不成比例地影响调节细胞形状和运动的途径。尽管融合蛋白在不同癌症类型中相似,但它们会影响癌症类型特异性通路。融合形成蛋白的关键指标包括高和非组织特异性表达、大量剪接位点以及在蛋白质相互作用网络中的较高中心性。总之,这些发现提供了不同致癌融合蛋白的统一和癌症类型特异性趋势。
更新日期:2019-04-01
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