Ethanol-induced formation of colorectal tumours and precursors in a mouse model of Lynch syndrome.
Ethanol-induced formation of colorectal tumours and precursors in a mouse model of Lynch syndrome.
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DOI：
10.1002/path.5796
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发表时间：
2021-12
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林奇综合征（LS）由于DNA错配修复（MMR）基因（例如MSH 2）中的种系突变而赋予遗传性癌症易感性。MMR是一种修复途径，用于去除由内源性和外源性因素引起的碱基错配和插入/缺失环。通过LS中野生型等位基因的体细胞改变导致的MMR缺失导致缺陷型MMR（dMMR）。生活方式/环境因素可以改变散发性和LS患者的结直肠癌风险。乙醇及其代谢物乙醛被归类为第一组致癌物，乙醛会导致一系列DNA损伤。然而，负责纠正大多数此类DNA损伤的DNA修复途径仍未被表征。我们假设MMR在保护结直肠上皮免受乙醇/乙醛诱导的DNA损伤中发挥作用。在此，使用LS小鼠模型（Msh 2的肠上皮条件性敲除）来确定dMMR和乙醇/乙醛之间是否存在加速LS中结直肠肿瘤发生的基因-环境相互作用。小鼠接受长期乙醇处理或水处理。大多数乙醇处理的小鼠在6个月内表现出结肠过度增殖和腺瘤形成（伴有一些侵袭性腺癌）（15/23，65%），相比之下，水处理的小鼠在15个月后出现1个结肠肿瘤（1/23，4%）（p < 0.0001，Fisher精确检验）。与水处理小鼠相比，在乙醇处理小鼠中观察到的dMMR结肠隐窝病灶前体数量显著更多（p = 0.0029，Student t检验）。此外，与水处理的小鼠相比，在乙醇处理的小鼠中检测到血浆乙醛水平增加（p = 0.0019，Mann-Whitney U-检验），沿着结肠上皮中DNA损伤反应显著增加。长期乙醇治疗与dMMR腺瘤中结肠上皮增殖显著增加和细胞凋亡显著减少相关，这与异常dMMR相对于MMR正常结肠上皮的生存率增加一致。总之，有强有力的证据表明，dMMR和乙醛之间存在基因-环境相互作用，导致该LS模型中dMMR驱动的结肠肿瘤形成加速，这表明应考虑LS患者限制饮酒的建议。版权所有© 2021作者。病理学杂志由John Wiley & Sons，Ltd.代表大不列颠和爱尔兰病理学会出版。
Lynch syndrome (LS) confers inherited cancer predisposition due to germline mutations in a DNA mismatch repair (MMR) gene, e.g. MSH2. MMR is a repair pathway for removal of base mismatches and insertion/deletion loops caused by endogenous and exogenous factors. Loss of MMR through somatic alteration of the wild‐type allele in LS results in defective MMR (dMMR). Lifestyle/environmental factors can modify colorectal cancer risk in sporadic and LS patients. Ethanol and its metabolite acetaldehyde are classified as group one carcinogens, and acetaldehyde causes a range of DNA lesions. However, DNA repair pathways responsible for correcting most of such DNA lesions remain uncharacterised. We hypothesised that MMR plays a role in protecting colorectal epithelium from ethanol/acetaldehyde‐induced DNA damage. Here, an LS mouse model (intestinal epithelial conditional‐knockout for Msh2) was used to determine if there is a gene–environment interaction between dMMR and ethanol/acetaldehyde that accelerates colorectal tumourigenesis in LS. Mice underwent either long‐term ethanol treatment or water treatment. Most ethanol‐treated mice demonstrated colonic hyperproliferation and adenoma formation (with some invasive adenocarcinomas) within 6 months (15/23, 65%), compared with one colonic tumour after 15 months in water‐treated mice (1/23, 4%) (p < 0.0001, Fisher's exact test). A significantly greater number of dMMR colonic crypt foci precursors were observed in ethanol‐treated compared with water‐treated mice (p = 0.0029, Student's t‐test). Moreover, increased plasma acetaldehyde levels were detected in ethanol‐treated compared with water‐treated mice (p = 0.0019, Mann–Whitney U‐test), along with significantly increased DNA damage response in the colonic epithelium. Long‐term ethanol treatment was associated with significantly increased colonic epithelial proliferation and markedly reduced apoptosis in dMMR adenomas, consistent with enhanced survival of aberrant dMMR relative to MMR‐proficient colonic epithelium. In conclusion, there is strong evidence for a gene–environment interaction between dMMR and acetaldehyde, causing acceleration of dMMR‐driven colonic tumour formation in this LS model, indicating that advice to limit alcohol consumption should be considered for LS patients. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
4.1
作者：
Kobel, Martin;Piskorz, Anna M;Lee, Sandra;Lui, Shuhong;LePage, Cecile;Marass, Francesco;Rosenfeld, Nitzan;Mes Masson, Anne-Marie;Brenton, James D
通讯作者：
Brenton, James D
影响因子：
3.8
作者：
Arnold A;Tronser M;Sers C;Ahadova A;Endris V;Mamlouk S;Horst D;Möbs M;Bischoff P;Kloor M;Bläker H
通讯作者：
Bläker H
影响因子：
4.3
作者：
Dai, Zhe;Xu, Yan-Cheng;Niu, Li
通讯作者：
Niu, Li
影响因子：
12.6
作者：
Leufkens, Anke M.;Van Duijnhoven, Franzel J. B.;Bueno-de-Mesquita, H. Bas
通讯作者：
Bueno-de-Mesquita, H. Bas