Department of Medicine, Dartmouth Medical School, Evergreen Center, Lebanon, NH 03756, USA.
Cancer Prev Res (Phila). 2010 Dec;3(12):1552-64. doi: 10.1158/1940-6207.CAPR-10-0047.
Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.
在衰老的正常组织中，一些基因的特异性启动子发生甲基化，这可能导致肿瘤发生。在本研究中，我们调查了血液叶酸水平以及饮食和生活方式因素与正常结直肠黏膜中 CpG 岛（CGI）甲基化的关系。研究对象被纳入阿司匹林或叶酸预防大肠腺瘤的多中心化学预防试验。我们从 389 名患者中收集了 1000 个活检标本，其中 501 个来自右半结肠，499 个来自直肠，在随访结肠镜检查时收集。我们使用亚硫酸氢盐焦磷酸测序法测量雌激素受体α（ERα）和分泌卷曲相关蛋白 1（SFRP1）的 DNA 甲基化。我们使用广义估计方程回归分析来研究甲基化与选定变量之间的关系。对于 ERα 和 SFRP1，直肠的甲基化百分比均显著高于右半结肠（P=0.001）。每增加 10 岁，我们观察到 ERα 的甲基化水平增加 1.7%，SFRP1 的甲基化水平增加 2.9%（P<0.0001）。与白人和西班牙裔相比，非裔美国人的 ERα 和 SFRP1 甲基化水平明显较低。较高的红细胞叶酸水平与 ERα（P=0.03）和 SFRP1 甲基化（P=0.01）水平较高相关。我们的研究结果表明，正常结直肠黏膜中的 CGI 甲基化与年龄增长、种族、直肠位置和红细胞叶酸水平有关。鉴于正常黏膜中的甲基化可能导致结直肠肿瘤发生的假说，这些数据对于健康成年人补充叶酸的安全性具有重要意义。
