Age-related somatic mutations in the cancer genome.
Age-related somatic mutations in the cancer genome.
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DOI：
10.18632/oncotarget.5685
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发表时间：
2015-09-22
期刊：
影响因子：
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通讯作者：
Vijg J
中科院分区：
文献类型：
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作者：
Milholland B;Auton A;Suh Y;Vijg J
衰老与癌症风险增加有关，部分原因可能是由于正常组织中与年龄相关的突变增加。由于其丰度极低，正常组织中的体细胞突变经常无法被发现。肿瘤作为单细胞的克隆扩增，可以提供有关肿瘤发生前这些细胞中存在的体细胞突变的信息。在这里，我们使用癌症基因组图谱 (TCGA) 的数据，系统地研究了总共 6,969 名患者和 34 种不同肿瘤类型的体细胞突变频率和谱与患者年龄的关系。在使用线性模型控制不同肿瘤类型的年龄结构后，我们发现已识别的体细胞突变数量随着年龄呈指数增加。利用文献中的其他数据，我们发现体细胞突变的积累与细胞分裂率、癌症风险和吸烟有关，后者还与一系列不同的突变有关。我们的研究结果证实，衰老与体细胞突变的积累有关，并强烈表明，受内源性和环境因素影响的正常细胞基因组不稳定性水平是癌症的主要危险因素。
Aging is associated with an increased risk of cancer, possibly in part because of an age-related increase in mutations in normal tissues. Due to their extremely low abundance, somatic mutations in normal tissues frequently escape detection. Tumors, as clonal expansions of single cells, can provide information about the somatic mutations present in these cells prior to tumorigenesis. Here, we used data from The Cancer Genome Atlas (TCGA), to systematically study the frequency and spectrum of somatic mutations in a total of 6,969 patients and 34 different tumor types as a function of the age of the patient. After using linear modeling to control for the age structure of different tumor types, we found that the number of identified somatic mutations increases exponentially with age. Using additional data from the literature, we found that accumulation of somatic mutations is associated with cell division rate, cancer risk and cigarette smoking, with the latter also associated with a distinct spectrum of mutations. Our results confirm that aging is associated with the accumulation of somatic mutations, and strongly suggest that the level of genome instability of normal cells, modified by both endogenous and environmental factors, is the main risk factor for cancer.