Association of Epigenetic Clock with Consensus Molecular Subtypes and Overall Survival of Colorectal Cancer

Epigenetic clock, or DNA methylation age, has been shown to highly correlate with chronologic age. Epigenetic age acceleration, the difference between DNA methylation age and individual's chronologic age, was observed in colorectal cancer. However, the association of epigenetic age acceleration with colorectal cancer tumor molecular characteristics, clinical characteristics, and patient outcomes has not been systematically investigated.

DNA methylation ages of 345 patients with colorectal cancer from The Cancer Genome Atlas (TCGA) were computed using the Horvath age prediction model. Multivariate linear regression was used to assess the association of epigenetic age acceleration with molecular and clinical features of colorectal cancer, including consensus molecular subtypes (CMS1-CMS4) and tumor stage Cox proportional hazards regression was used to assess the association of epigenetic age acceleration with survival.

Epigenetic age acceleration is significantly associated with CMS. Compared with CMS2, epigenetic age acceleration for CMS1, CMS3, and CMS4 was 23.90 years [P = 5.55E-11; 95% confidence interval (CI): 17.10-30.69], 9.16 years (P = 5.84E-03; 95% CI: 2.68-15.65), and 6.05 years (P = 2.69E-02; 95% CI: 0.70-11.41), respectively. Furthermore, epigenetic age acceleration is statistically significantly and positively associated with total mortality (HR = 1.97; 95% CI: 1.14-3.39; P = 0.014).

Epigenetic age acceleration is associated with colorectal cancer tumor molecular characteristics, and a significant predictor of overall survival of colorectal cancer, along with age and tumor stage.

Combining information of colonic tissue epigenetic age acceleration and tumor molecular characteristics may improve prognosis prediction in colorectal cancer.