Long-term aspirin use and epigenetic mitotic clocks for cancer risk prediction: findings in healthy colon mucosa and recommendations for future epigenetic aging studies

Abstract

Background 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). 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. Findings EpiTOC, 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). Conclusions Our 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.

Open access-enabled evaluation of epigenetic age acceleration in colorectal cancer and development of a classifier with diagnostic potential

“…Since DNAm alteration is associated with cancer incidence, epigenetic age scores have been studied to find suitable DNAm markers for cancer, including CRC. Previous studies have assessed the relationship between CRC and EAA (Durso et al (2017); Zheng et al (2019); Devall et al (2021); Nwanaji-Enwerem et al (2021); Matas et al (2022)).…”

“…Since DNAm alteration is associated with cancer incidence, epigenetic age scores have been studied to find suitable DNAm markers for cancer, including CRC. Previous studies have assessed the relationship between CRC and EAA (Durso et al (2017); Zheng et al (2019); Devall et al (2021); Nwanaji-Enwerem et al (2021); Matas et al (2022)). However, our understanding of whether epigenetic ageing measures (EA and/or EAA) differ between histologically normal colon tissues in individuals with and without CRC is limited to two publications (Joo et al (2021); Wang et al (2020)).…”