Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland.
Swiss Institute of Bioinformatics, 4053, Basel, Switzerland.
Clin Epigenetics. 2020 Nov 3;12(1):164. doi: 10.1186/s13148-020-00956-9.
Colon cancer (CC) is the third most common cancer worldwide, highlighting the importance of developing effective prevention strategies. Accumulating evidence supports that aspirin use reduces CC incidence. We reported previously that aspirin suppresses age-associated and CC-relevant DNA methylation (DNAm) in healthy colon. Here we addressed the aspirin's effectiveness in longitudinal cohort.
We measured genome-wide DNAm in 124 healthy normal mucosa samples taken at baseline (time point 1, t1) and after 10-years follow-up (time point 2, t2) from a longitudinal female screening cohort. We investigated the time-dependent methylation drift in aspirin users and nonusers using multivariable regression and related the modulatory effect of aspirin to colonic epigenome-aging and CC.
Over time, compared to nonusers, long-term (≥ 2 years) aspirin users showed less hypermethylated CpGs (proximal: 17% vs. 87%; distal: 16% vs. 70%) and more hypomethylated CpGs (proximal: 83% vs. 13%; distal: 84% vs. 30%). Overall, users showed 2% (P = 0.02) less mean methylation levels than nonusers in proximal colon and displayed repressed methylation age (mAge). Methylation loss in users occurred at several CC-specific tumor suppressors that gained methylation in nonusers. Methylation loss in users effected genes involved in immune system and inflammation, while methylation gain in nonusers effected genes involved in metabolism.
This is the first longitudinal study demonstrating effectiveness of aspirin-use in suppression of age-related and CC-relevant hypermethylation in the normal colon. These findings provide a rationale for future studies to evaluate loci that may serve as markers to identify individuals that will benefit most from aspirin and hence increase its efficiency in CC prevention and therapy.
结肠癌（CC）是全球第三大常见癌症，这凸显了开发有效预防策略的重要性。越来越多的证据表明，阿司匹林的使用可以降低 CC 的发病率。我们之前曾报道过，阿司匹林可以抑制健康结肠中与年龄相关和 CC 相关的 DNA 甲基化（DNAm）。在这里，我们在纵向队列中研究了阿司匹林的疗效。
我们在一个女性筛查队列中，从 124 名健康正常黏膜样本中测量了全基因组 DNAm，这些样本是在基线（时间点 1，t1）和 10 年随访（时间点 2，t2）时采集的。我们使用多变量回归研究了阿司匹林使用者和非使用者的时间依赖性甲基化漂移，并将阿司匹林的调节作用与结肠表观遗传衰老和 CC 相关联。
随着时间的推移，与非使用者相比，长期（≥2 年）阿司匹林使用者表现出较少的超甲基化 CpG（近端：17%对 87%；远端：16%对 70%）和更多的低甲基化 CpG（近端：83%对 13%；远端：84%对 30%）。总体而言，与非使用者相比，使用者在近端结肠的平均甲基化水平低 2%（P=0.02），并显示出抑制的甲基化年龄（mAge）。使用者中的甲基化丢失发生在几个 CC 特异性肿瘤抑制基因上，这些基因在非使用者中获得了甲基化。使用者中的甲基化丢失影响了免疫系统和炎症相关的基因，而非使用者中的甲基化获得则影响了代谢相关的基因。
这是第一项证明阿司匹林使用对正常结肠中与年龄相关和 CC 相关的高甲基化有抑制作用的纵向研究。这些发现为未来的研究提供了依据，以评估可能作为标记物的基因，以识别最受益于阿司匹林的个体，并因此提高阿司匹林在 CC 预防和治疗中的效率。
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