Universal Patterns of Selection in Cancer and Somatic Tissues.
Universal Patterns of Selection in Cancer and Somatic Tissues.
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DOI：
10.1016/j.cell.2017.09.042
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发表时间：
2017-11-16
期刊：
影响因子：
64.5
通讯作者：
Campbell PJ
中科院分区：
文献类型：
--
作者：
Martincorena I;Raine KM;Gerstung M;Dawson KJ;Haase K;Van Loo P;Davies H;Stratton MR;Campbell PJ
癌症的发展是体细胞突变和克隆选择的结果，但缺乏癌症进化中选择的定量测量。我们改编了分子进化的方法，并将其应用于29种癌症类型的7664种肿瘤。与物种进化不同，在癌症发展过程中，积极选择多于消极选择。平均而言，负选择损失<1个编码碱基置换/肿瘤，除必需基因纯合子损失外，几乎不存在纯化选择。这允许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的<1/肿瘤到子宫内膜癌和结直肠癌的bb10 /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了分类，并表明基因在驱动者和乘客的突变比例上差异很大。与生殖系不同，体细胞主要通过正选择进化，几乎所有（~ 99%）编码突变都是耐受的，并逃避负选择。每个肿瘤驱动编码突变总数的外显子组范围估计，一半的编码驱动突变发生在已知的癌症基因之外。将进化基因组学方法应用于癌症，强调了负选择对癌症基因组的有限影响，以及不同肿瘤中编码驱动突变比例的显著差异不同的肿瘤类型。
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. Unlike the germline, somatic cells evolve predominantly by positive selection Nearly all (∼99%) coding mutations are tolerated and escape negative selection Exome-wide estimates of the total number of driver coding mutations per tumor Half of the coding driver mutations occur outside of known cancer genes Adapting an evolutionary genomics approach to cancer highlights a limited impact of negative selection on cancer genomes and significant variations in the proportion of coding driver mutations per tumor among different tumor types.
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影响因子：
64.5
作者：
Haradhvala NJ;Polak P;Stojanov P;Covington KR;Shinbrot E;Hess JM;Rheinbay E;Kim J;Maruvka YE;Braunstein LZ;Kamburov A;Hanawalt PC;Wheeler DA;Koren A;Lawrence MS;Getz G
通讯作者：
Getz G
影响因子：
56.9
作者：
Blomen, Vincent A.;Majek, Peter;Brummelkamp, Thijn R.
通讯作者：
Brummelkamp, Thijn R.
影响因子：
3.5
作者：
Church DN;Briggs SE;Palles C;Domingo E;Kearsey SJ;Grimes JM;Gorman M;Martin L;Howarth KM;Hodgson SV;NSECG Collaborators;Kaur K;Taylor J;Tomlinson IP
通讯作者：
Tomlinson IP
影响因子：
56.9
作者：
Galloway, Alison;Saveliev, Alexander;Turner, Martin
通讯作者：
Turner, Martin
影响因子：
82.9
作者：
Hanse, Ronald J.;Pritchard, Colin C.;Salipante, Stephen J.
通讯作者：
Salipante, Stephen J.