Abstract
BackgroundDespite the known role of mitosis in colorectal cancer, previous associations of long-term aspirin use with suppressed cancer-related epigenetic aging did not involve epigenetic mitotic clocks. We investigated these relationships using three epigenetic mitotic clocks developed for cancer risk prediction: EpiTOC, EpiTOC2, and MiAge. We utilized publicly available HumanMethylationEPIC BeadChip data from 112 healthy colon (proximal and distal) mucosal samples taken at baseline (T1) and at 10-years follow-up (T2) from a screening cohort of 28 Polish women (11 non-users and 17 long-term [≥ 2 years] aspirin users). Mitotic clock values were divided by chronological age at each timepoint to obtain intrinsic rates (IRs). We evaluated differences in residuals of the mitotic clock IRs taken from linear mixed effects models adjusted for BMI, polyp status, and DNA methylation batch.FindingsEpiTOC, EpiTOC2, and MiAge were significantly correlated with chronological age (P < 0.05) with correlations ranging from 0.41 to 0.63. The EpiTOC, EpiTOC2, and MiAge clocks were strongly correlated with each other in proximal and distal samples (r > 0.79, P < 0.0001). We observed proximal within group median clock IR deceleration for EpiTOC (-0.0004 DNAm, P = 0.008), EpiTOC2 (− 16 cell divisions, P = 0.009), and MiAge (− 3 cell divisions, P = 0.002) for long-term aspirin users from T1 to T2 but not for non-users. In distal samples, only the long-term user MiAge IR was significantly deaccelerated (− 3 cell divisions, P = 0.009).ConclusionsOur observed findings support previously reported longitudinal associations of aspirin use with deceleration of other epigenetic age measures in the proximal colon. Our mitotic clock results suggest that cell proliferation could play a role in some aspirin relationships with epigenetic aging. Furthermore, the findings provide added impetus for establishing gold standards for epigenetic aging and consensus guidelines for more comprehensive reporting in future epigenetic aging cancer studies.
Highlights
Existing data, including evidence from human randomized controlled trials, suggests that aspirin may be protective against colorectal cancer (CRC) in certain populations [1,2,3]
Our mitotic clock results suggest that cell proliferation could play a role in some aspirin relationships with epigenetic aging
Understanding aspirin and CRC relationships with mitotic clocks is important given that deviations from chronological age captured by many of the other epigenetic clocks are independent of cell proliferation [14]
Summary
Existing data, including evidence from human randomized controlled trials, suggests that aspirin may be protective against colorectal cancer (CRC) in certain populations [1,2,3]. Despite the optimism surrounding the role that aspirin may play as a CRC chemopreventive agent, issues of long-term patient drug adherence, therapeutic contraindications, and CRC’s existing immense morbidity—the third most common cancer diagnosed globally with an estimated 1.8 million new cases annually [5]—guarantee a continued need for disease screening and surveillance [1] For this reason, it will be important to characterize the relationship of aspirin use with CRC screening and surveillance modalities. Despite the known role of mitosis in colorectal cancer, previous associations of long-term aspirin use with suppressed cancer-related epigenetic aging did not involve epigenetic mitotic clocks We investigated these relationships using three epigenetic mitotic clocks developed for cancer risk prediction: EpiTOC, EpiTOC2, and MiAge. We utilized publicly available HumanMethylationEPIC BeadChip data from 112 healthy colon (proximal and distal) mucosal samples taken at baseline (T1) and at 10-years follow-up (T2) from a screening cohort of 28 Polish women (11 non-users and 17 long-term [≥ 2 years] aspirin users). We evaluated differences in residuals of the mitotic clock IRs taken from linear mixed effects models adjusted for BMI, polyp status, and DNA methylation batch
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