Barrow Timothy M, Klett Hagen, Toth Reka, Böhm Jürgen, Gigic Biljana, Habermann Nina, Scherer Dominique, Schrotz-King Petra, Skender Stephanie, Abbenhardt-Martin Clare, Zielske Lin, Schneider Martin, Ulrich Alexis, Schirmacher Peter, Herpel Esther, Brenner Hermann, Busch Hauke, Boerries Melanie, Ulrich Cornelia M, Michels Karin B
German Cancer Consortium (DKTK), Heidelberg, Germany.
Institute for Prevention and Cancer Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
J Pathol. 2017 Nov;243(3):366-375. doi: 10.1002/path.4955. Epub 2017 Sep 29.
Smoking tobacco is a known risk factor for the development of colorectal cancer and for mortality associated with the disease. Smoking has been reported to be associated with changes in DNA methylation in blood and in lung tumour tissues, although there has been scant investigation of how epigenetic factors may be implicated in the increased risk of developing colorectal cancer. To identify epigenetic changes associated with smoking behaviours, we performed epigenome-wide analysis of DNA methylation in colorectal tumours from 36 never-smokers, 47 former smokers, and 13 active smokers, and in adjacent mucosa from 49 never-smokers, 64 former smokers, and 18 active smokers. Our analyses identified 15 CpG sites within the APC 1A promoter that were significantly hypermethylated and 14 CpG loci within the NFATC1 gene body that were significantly hypomethylated (pLIS < 1 × 10 ) in the tumours of active smokers. The APC 1A promoter was hypermethylated in 7 of 36 tumours from never-smokers (19%), 12 of 47 tumours from former smokers (26%), and 8 of 13 tumours from active smokers (62%). Promoter hypermethylation was positively associated with duration of smoking (Spearman rank correlation, ρ = 0.26, p = 0.03) and was confined to tumours, with hypermethylation never being observed in adjacent mucosa. Further analysis of adjacent mucosa revealed significant hypomethylation of four loci associated with the TNXB gene in tissue from active smokers. Our findings provide exploratory evidence for hypermethylation of the key tumour suppressor gene APC being implicated in smoking-associated colorectal carcinogenesis. Further work is required to establish the validity of our observations in independent cohorts. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
吸烟是已知的结直肠癌发生及与该疾病相关死亡率的风险因素。据报道，吸烟与血液及肺肿瘤组织中的DNA甲基化变化有关，尽管关于表观遗传因素如何可能与结直肠癌发病风险增加有关的研究很少。为了确定与吸烟行为相关的表观遗传变化，我们对36名从不吸烟者、47名既往吸烟者和13名当前吸烟者的结直肠肿瘤以及49名从不吸烟者、64名既往吸烟者和18名当前吸烟者的相邻黏膜进行了全表观基因组DNA甲基化分析。我们的分析确定，在当前吸烟者的肿瘤中，APC 1A启动子内有15个CpG位点显著高甲基化，NFATC1基因体内有14个CpG位点显著低甲基化（pLIS＜1×10）。APC 1A启动子在36名从不吸烟者的36个肿瘤中的7个（19%）、47名既往吸烟者的47个肿瘤中的12个（26%）以及13名当前吸烟者的13个肿瘤中的8个（62%）中发生高甲基化。启动子高甲基化与吸烟持续时间呈正相关（Spearman等级相关性，ρ = 0.26，p = 0.03），且仅限于肿瘤，在相邻黏膜中从未观察到高甲基化。对相邻黏膜的进一步分析显示，当前吸烟者组织中与TNXB基因相关的四个位点存在显著低甲基化。我们的研究结果为关键肿瘤抑制基因APC的高甲基化参与吸烟相关的结直肠癌发生提供了探索性证据。需要进一步开展工作以在独立队列中证实我们观察结果的有效性。版权所有© 2017英国及爱尔兰病理学会。由John Wiley & Sons, Ltd.出版。
