Abstract
BackgroundChronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual’s susceptibility to age-related diseases such as CRC.MethodsWe conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual’s chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk.ResultsEach epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10−30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group.ConclusionsAmong the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.
Highlights
Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC)
Assessment of epigenetic clocks in normal colon mucosa To study epigenetic aging in the normal colon and its correlation with the risk for developing colorectal cancer, we conducted a genome-wide DNA methylation study on normal colon mucosa samples collected from patients assigned to the low, medium, and high CRC risk groups (N = 105, 128, and 101, respectively, see Table 1 for subject information)
Our observations demonstrate that the Horvath clock is the most accurate clock for predicting the chronological age in the normal colon and that the epigenetic ages derived from the Hannum, PhenoAge, Fig. 1 Correlation of four epigenetic age estimates (Hannum, Horvath, PhenoAge, and EpiTOC) in the normal colon with the chronological age of the individuals providing the normal colon samples
Summary
Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). DNA methylation alterations commonly occur in adenomas and CRCs and appear to cooperate with gene mutations to mediate field cancerization ( known as “field effect” or “field defect”) in the colon and induce the initiation and progression of adenomas [3,4,5,6,7,8,9]. Previous studies evaluating methylation in the (2020) 12:5 normal-appearing colon mucosa have demonstrated an association between DNA methylation of certain cancerrelated genes and neoplastic lesions located elsewhere in the colon [10,11,12,13]. DNA methylation alterations in the normal colon mucosa could serve as epigenetic markers for colon adenoma and/or CRC risk
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