A diffusion-like process enables expansion of advantaged gene mutations in human colonic epithelium
A diffusion-like process enables expansion of advantaged gene mutations in human colonic epithelium
复制标题
类似扩散的过程能够扩展人类结肠上皮中的有利基因突变
DOI：
10.1101/2020.07.10.193748
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Olpe C
中科院分区：
文献类型：
--
作者：
Olpe C
结肠直肠癌被认为是当结肠隐窝内干细胞克隆群体的突变负荷超过一定阈值时发生的。因此，量化组织学正常上皮细胞中体细胞突变的固定和随后的扩展是理解结直肠癌发生的关键。在这里，使用免疫组织化学，组蛋白去甲基化酶KDM6A在正常人结肠上皮细胞的损失是可视化的。KDM6A阴性克隆的年龄相关行为的解释揭示了在隐窝内动态中的显着竞争优势。此外，随后的克隆扩增到多隐窝补丁进行了定量，揭示了一个显着的5倍增加隐窝分裂率。为了适应新隐窝的局部积累，考虑了隐窝融合的作用。然而，没有发现融合率的补偿性增加，相反，提出了隐窝扩散的证据，并提出作为一种适应克隆扩张的手段。阈值裂变率扩散未能容纳新的隐窝，这可能会促进息肉生长，被定义。
Colorectal cancer is thought to arise when the mutational burden of the clonal population of stem cells within a colonic crypt exceeds a certain threshold. Therefore, quantification of the fixation and subsequent expansion of somatic mutations in histologically normal epithelium is key to understanding colorectal cancer initiation. Here, using immunohistochemistry, loss of the histone demethylase KDM6A in normal human colonic epithelium is visualised. Interpretation of the age-related behaviour of KDM6A-negative clones revealed significant competitive advantage in intra-crypt dynamics. Further, subsequent clonal expansion into multi-crypt patches was quantified to reveal a significant 5-fold increase in crypt fission rate. To accomodate the local accumulation of new crypts, the role of crypt fusion was considered. However, no compensatory increase in fusion rate was found. Instead, evidence for crypt diffusion is presented and proposed as a means of accommodating clonal expansions. The threshold fission rate at which diffusion fails to accommodate new crypts, and which may promote polyp growth, is defined.
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KRAS 基因突变在结直肠绒毛状腺瘤和原位癌中比在癌中更常见。
DOI：
--
发表时间：
2013
期刊：
International Journal of Molecular Epidemiology and Genetics
影响因子：
--
作者：
P. Zauber;S. Marotta;M. Sabbath‐Solitare
通讯作者：
M. Sabbath‐Solitare
影响因子：
24.5
作者：
W. Wong;N. Mandir;R. Goodlad;B. Wong;S. Garcia;S. Lam;N. Wright
通讯作者：
W. Wong;N. Mandir;R. Goodlad;B. Wong;S. Garcia;S. Lam;N. Wright
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
影响因子：
23.9
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
通讯作者：
Winton DJ
影响因子：
--
作者：
CHENG, H;MCCULLOCH, C;BJERKNES, M
通讯作者：
BJERKNES, M