Studying Tumorigenesis through Network Evolution and Somatic Mutational Perturbations in the Cancer Interactome
Studying Tumorigenesis through Network Evolution and Somatic Mutational Perturbations in the Cancer Interactome
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DOI：
10.1093/molbev/msu167
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发表时间：
2014-08-01
影响因子：
10.7
通讯作者：
Zhao, Zhongming
中科院分区：
文献类型：
--
作者：
Cheng, Feixiong;Jia, Peilin;Zhao, Zhongming
细胞通过复杂的生物网络控制生物功能。网络的扰动可能驱动细胞进入新的表型状态，例如，肿瘤发生。确定遗传病变如何扰乱分子网络是一个根本性的挑战。本研究利用大规模人类相互作用组数据，系统探讨了肿瘤基因的网络拓扑结构、体细胞突变、进化速率和进化起源之间的关系。我们发现了癌症蛋白独特的网络中心性，这在很大程度上独立于基因的必要性。与非癌症基因、孟德尔病基因和孤儿病基因相比，癌症基因可能经历了更低的进化速率和更强的净化选择。癌症蛋白往往具有古老的历史，可能起源于早期后生动物，尽管它们比孟德尔病基因、孤儿病基因和必需基因编码的蛋白质更年轻。我们发现蛋白质的进化起源（年龄）与人类相互作用组中的蛋白质连接呈正相关。此外，我们研究了来自癌症基因组图谱中12种癌症类型的3268个肿瘤的体细胞突变引起的网络攻击扰动。我们观察到蛋白质连通性与非同义体细胞突变数量之间呈正相关，而蛋白质连通性与同义体细胞突变数量之间的相关性较弱或不显著。这些观察结果表明，对枢纽基因的体细胞突变网络攻击扰动在肿瘤的发生和进化中起着重要作用。总的来说，这项工作对基础癌症生物学和个性化癌症治疗的发展具有广泛的生物医学意义。
Cells govern biological functions through complex biological networks. Perturbations to networks may drive cells to new phenotypic states, for example, tumorigenesis. Identifying how genetic lesions perturb molecular networks is a fundamental challenge. This study used large-scale human interactome data to systematically explore the relationship among network topology, somatic mutation, evolutionary rate, and evolutionary origin of cancer genes. We found the unique network centrality of cancer proteins, which is largely independent of gene essentiality. Cancer genes likely have experienced a lower evolutionary rate and stronger purifying selection than those of noncancer, Mendelian disease, and orphan disease genes. Cancer proteins tend to have ancient histories, likely originated in early metazoan, although they are younger than proteins encoded by Mendelian disease genes, orphan disease genes, and essential genes. We found that the protein evolutionary origin (age) positively correlates with protein connectivity in the human interactome. Furthermore, we investigated the network-attacking perturbations due to somatic mutations identified from 3,268 tumors across 12 cancer types in The Cancer Genome Atlas. We observed a positive correlation between protein connectivity and the number of nonsynonymous somatic mutations, whereas a weaker or insignificant correlation between protein connectivity and the number of synonymous somatic mutations. These observations suggest that somatic mutational network-attacking perturbations to hub genes play an important role in tumor emergence and evolution. Collectively, this work has broad biomedical implications for both basic cancer biology and the development of personalized cancer therapy.