epiTOC2

epiTOC2 estimates mitotic age from genome-wide DNA methylation profiles to infer cumulative stem-cell divisions and tissue-specific mitotic rate changes relevant to cancer risk.

Key Features:

• Mitotic clock model: Uses a dynamic model of DNA methylation gain in unmethylated CpG-rich regions where methylation errors accumulate with cell division.
• Estimation capabilities: Estimates cumulative number of stem-cell divisions (mitotic age) and calculates intrinsic stem-cell division rate per year when chronological age is provided.
• Comparison with other models: Has been compared to HypoClock, which relies on hypomethylation at solo-WCGW sites, and reported more accurate and robust mitotic age estimates in normal adult tissues.
• Implementation: Provided as an R script that analyzes genome-wide DNA methylation profiles.
• Robustness under replicative stress: Maintains performance under conditions of high replicative stress where alternative models such as HypoClock may underperform.

Scientific Applications:

• Cancer risk prediction: Infers tissue- and individual-level variation in cancer risk by estimating cumulative stem-cell divisions and elevated mitotic rates associated with cancer.
• Preneoplastic lesion discrimination: Distinguishes preneoplastic lesions characterized by chronic inflammation that are associated with increased tissue turnover.
• Validation and correlation: Estimated intrinsic stem-cell division rates show strong agreement with experimental data (Pearson correlation = 0.92, R² = 0.85, P = 3e-6).
• Diagnostic assay potential: Identifies CpGs whose methylation measurements could form the basis for pre-diagnostic or cancer risk assays, including applications in serum cell-free DNA.

Methodology:

Analyzes genome-wide DNA methylation profiles at unmethylated CpG-rich regions using a dynamic model of methylation gain to estimate cumulative stem-cell divisions and, when chronological age is provided, intrinsic division rate per year.