Abstract
BackgroundColon 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.MethodsWe 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.ResultsOver 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.ConclusionsThis 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.
Highlights
Colon cancer (CC) is the third most common cancer worldwide, highlighting the importance of developing effective prevention strategies
Principal component analysis (PCA) on methylation profiles separated proximal from distal colon samples (28% variation), aspirin users (U) from nonusers (Nu) and/or t1 from t2 (8% variation) (Fig. 1a)
Multivariable linear regression model was used to measure significant differentially methylated CpGs in aspirin users (U-dmCpGs) and in nonusers (Nu-dmCpGs) from t1 to t2.We identified more hypomethylated U-dmCpGs in aspirin users and more hypermethylated Nu-dmCpGs in nonusers (Fig. 1b, Additional file 1: Figure S1a)
Summary
Colon cancer (CC) is the third most common cancer worldwide, highlighting the importance of developing effective prevention strategies. We reported previously that aspirin suppresses age-associated and CC-relevant DNA methylation (DNAm) in healthy colon. Noreen et al Clin Epigenet (2020) 12:164 action is important to increase its benefit-risk ratio, given the known hazards of its use [8,9,10]. Epigenetic modifications, DNA methylation (DNAm) changes, are recognized as one of the most common molecular alterations in human tumors, including CC [15]. The stability of DNAm on as molecular marker and its effect on gene expression [20] facilitates its clinical use in early cancer detection and makes it a potential target to predict treatment outcome and patient’s response to therapy
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