Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium.
Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium.
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DOI：
10.1016/j.stem.2018.04.020
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发表时间：
2018-06-01
期刊：
影响因子：
23.9
通讯作者：
Winton DJ
中科院分区：
文献类型：
--
作者：
Nicholson AM;Olpe C;Hoyle A;Thorsen AS;Rus T;Colombé M;Brunton-Sim R;Kemp R;Marks K;Quirke P;Malhotra S;Ten Hoopen R;Ibrahim A;Lindskog C;Myers MB;Parsons B;Tavaré S;Wilkinson M;Morrissey E;Winton DJ
我们通过可视化体细胞克隆和数学推理研究了突变在人类结肠上皮中固定的方式和时间。固定需要两个连续的步骤。首先，每个结肠隐窝内大约有7个活性干细胞，其中一个必须发生突变。其次，突变的干细胞必须取代相邻的细胞来填充整个隐窝，这一过程需要数年时间。在中性突变中，由于隐窝裂变引起的后续克隆扩增并不常见（在一年内约有0.7%的隐窝发生裂变）。前致癌突变破坏干细胞替代，加速固定和克隆扩增，通过隐窝裂变实现高突变等位基因频率。这些行为的基准允许与不同基因特异性突变相关的优势进行比较，而不考虑它们被授予的细胞机制。结肠干细胞动力学预测寿命突变等位基因频率突变克隆在结肠隐窝中的固定需要数年时间，因为干细胞更新缓慢隐窝裂变使突变克隆的横向扩展，固定和扩展的偏见增加了年龄相关的促癌负担Winton和他的同事描述了正常人类结肠中的干细胞动力学，以确定克隆在上皮内固定的效率和随后的横向扩展率。根据这些基准，有偏见的干细胞行为在固定和扩增方面都具有优势，可以量化以预测与年龄相关的促癌突变负担。
We investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated. Second, the mutated stem cell has to replace neighbors to populate the entire crypt in a process that takes several years. Subsequent clonal expansion due to crypt fission is infrequent for neutral mutations (around 0.7% of all crypts undergo fission in a single year). Pro-oncogenic mutations subvert both stem cell replacement to accelerate fixation and clonal expansion by crypt fission to achieve high mutant allele frequencies with age. The benchmarking of these behaviors allows the advantage associated with different gene-specific mutations to be compared irrespective of the cellular mechanisms by which they are conferred. Colonic stem cell dynamics predict lifetime mutant allele frequencies Mutant clone fixation in colonic crypts takes years due to slow stem cell turnover Crypt fission enables lateral expansion of mutant clones Biases in both fixation and expansion increase age-related pro-oncogenic burden Winton and colleagues describe stem cell dynamics in normal human colon to identify the efficiency of clone fixation within the epithelium and the rate of subsequent lateral expansion. Against these benchmarks biased stem cell behaviors advantaged in both fixation and expansion can be quantified to predict the age-related burden of pro-oncogenic mutation.
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DOI：
10.1016/j.bbcan.2016.05.002
发表时间：
2016-08
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Hill VK;Kim JS;Waldman T
通讯作者：
Waldman T
体内成像显示成年小鼠肠道中存在隐窝分裂和融合现象
影响因子：
29.4
作者：
Bruens L;Ellenbroek SIJ;van Rheenen J;Snippert HJ
通讯作者：
Snippert HJ
DOI：
10.1126/science.1242281
发表时间：
2014-06-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Blanpain C;Fuchs E
通讯作者：
Fuchs E
DOI：
10.1073/pnas.0505903103
发表时间：
2006-01-17
影响因子：
11.1
作者：
Greaves, LC;Preston, SL;McDonald, SAC
通讯作者：
McDonald, SAC
影响因子：
29.4
作者：
Galandiuk, Susan;Rodriguez-Justo, Manuel;Graham, Trevor A.
通讯作者：
Graham, Trevor A.