Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk

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.

Development and validation of a five-immune gene prognostic risk model in colon cancer

“…Age, the pathological stage, and the risk score were identified as independent prognostic variables. Age is a prominent risk factor for multiple tumors including colorectal cancer [24], which was in line with the results predicted by the model. Further comparison showed that the predicted value of the model is better than age and the pathological stage.…”

Longitudinal analysis of healthy colon establishes aspirin as a suppressor of cancer-related epigenetic aging

“…Epigenetic modifications, particularly DNA methylation (DNAm) changes, are recognized as one of the most common molecular alterations in human tumors, including CC [ 15 ]. CC-subtype-specific DNAm are readily detectable in healthy normal mucosa [ 16 – 18 ], before the occurrence of visible precursor lesions, which ultimately may progress to CC [ 19 ]. 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.…”

Epigenetic Aging and Colorectal Cancer: State of the Art and Perspectives for Future Research

“…In fact, other studies have estimated the epigenetic age of colonic mucosa to identify the factors that associated with biological aging, CRC risk, and specific molecular subtypes. For instance, Wang and colleagues analyzed the genome-wide DNA methylation profile of normal colon mucosa from 334 subjects, categorized at low, medium, or high risk for CRC, according to personal and clinical characteristics [ 57 ]. They used the Hannum’s, Horvath’s, DNAm PhenoAge, and EpiTOC methods to assess epigenetic age and Δage.…”

“…Among all of the DNA methylation-based age estimators considered, Horvath’s clock exhibited the highest correlation coefficient with chronological age. According to DNAm PhenoAge, instead, patients at high-risk for CRC showed a higher Δage than those collocated in the other groups [ 57 ]. By contrast, Zheng and colleagues used Horvath’s clock to estimate the epigenetic age of colonic mucosa from 345 CRC patients and to investigate its association with other molecular features, clinical characteristics, and patients’ prognosis [ 58 ].…”