Tissue-specific Mitotic Clocks Link Cumulative Stem Cell Divisions to Human Cancer Susceptibility

Why cancer risk varies so dramatically across human tissues remains a fundamental question in oncology. While this variation has been linked to differences in total stem cell divisions (TNSD), molecular tools for measuring tissue-specific proliferative history are lacking. Existing DNA methylation-based mitotic clocks conflate chronological aging with mitotic activity and apply pan-tissue assumptions that obscure tissue-level turnover dynamics. Here, we develop tissue-specific mitotic clocks for six major tissues by modeling global hypomethylation at solo-WCGW CpG sites within partially methylated domains (PMDs) — an experimentally validated, age-independent marker of cumulative cell division — using biologically normal tissue from the Genotype-Tissue Expression (GTEx) project. This design explicitly avoids confounding from chronological age and field cancerization. Our tissue-specific clocks demonstrate strong generalizability, replicate across independent cohorts, and outperform existing pan-tissue clocks in recapitulating Vogelstein and Tomasetti-derived (2017) TNSD estimates and SEER cancer incidence data. These results provide direct molecular evidence that cumulative cellular turnover underlies tissue cancer susceptibility, and establish a precision framework for quantifying proliferative burden in human malignancies — with implications for cancer risk stratification, prevention, and mechanistic dissection of replication-driven versus exposure-related carcinogenesis.