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Universal Patterns of Selection in Cancer and Somatic Tissues.
Cell ( IF 64.5 ) Pub Date : 2017-Nov-16 , DOI: 10.1016/j.cell.2017.09.042
Iñigo Martincorena 1 , Keiran M Raine 1 , Moritz Gerstung 2 , Kevin J Dawson 1 , Kerstin Haase 3 , Peter Van Loo 4 , Helen Davies 1 , Michael R Stratton 1 , Peter J Campbell 5
Affiliation  

Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.

中文翻译:

癌症和体细胞组织中的通用选择模式。

癌症的发展是体细胞突变和克隆选择的结果,但缺乏对癌症进化中选择的定量测量。我们采用了分子进化的方法,并将它们应用于 29 种癌症类型的 7,664 个肿瘤。与物种进化不同,在癌症发展过程中,正选择胜过负选择。平均而言,<1 个编码碱基替换/肿瘤通过负选择丢失,纯化选择几乎不存在于必需基因的纯合丢失之外。这允许在外显子组范围内枚举所有驱动编码突变,包括外部已知的癌症基因。平均而言,肿瘤在阳性选择下携带约 4 个编码替换,范围从甲状腺癌和睾丸癌中的<1/肿瘤到子宫内膜癌和结直肠癌中的>10/肿瘤。一半的驱动替换发生在尚未发现的癌症基因中。随着突变负担的增加,驱动突变的数量增加,但不是线性的。我们系统地对癌症基因进行分类,并表明基因在突变的比例是司机还是乘客方面差异很大。
更新日期:2017-10-19
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