Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk

Ting Wang, Sean K Maden, Georg E Luebeck, Christopher I Li, Polly A Newcomb, Cornelia M Ulrich, Ji-Hoon E Joo, Daniel D Buchanan, Roger L Milne, Melissa C Southey, Kelly T Carter, Amber R Willbanks, Yanxin Luo, Ming Yu, William M Grady, Ting Wang, Sean K Maden, Georg E Luebeck, Christopher I Li, Polly A Newcomb, Cornelia M Ulrich, Ji-Hoon E Joo, Daniel D Buchanan, Roger L Milne, Melissa C Southey, Kelly T Carter, Amber R Willbanks, Yanxin Luo, Ming Yu, William M Grady

Abstract

Background: Chronological 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.

Methods: We 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.

Results: Each 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.

Conclusions: Among 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.

Keywords: Biological/epigenetic age; Colorectal cancer; DNA methylation; Epigenetic age acceleration; Epigenetic clock.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
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. Different colors represent different groups based on the CRC risk status
Fig. 2
Fig. 2
Distribution of epigenetic age acceleration in the three CRC risk groups. The y-axis shows the epigenetic age acceleration after adjusting for gender and cell-type fractions (i.e., residual of regressing the epigenetic age acceleration on gender and cell-type fractions). Standardized effect size (i.e., Cohen’s d) and p value for the significant association (p value < 0.01) is shown above the corresponding line

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