Correlation of a pan-tissue epigenetic mitotic clock with tumor cell-of-origin

Abstract The cumulative number of stem cell divisions in a tissue, also known as mitotic age, is thought to be a major determinant of cancer-risk. Somatic mutational and DNA methylation (DNAm) clocks are promising tools to molecularly track mitotic age, yet their relationship is unexplored and their potential for cancer risk prediction in the tumor cell-of-origin remains to be demonstrated. Using advanced cell-type deconvolution methods in conjunction with a novel pan-tissue epigenetic mitotic clock called stemTOC, we here demonstrate that a sample’s mitotic age correlates with its putative tumor cell-of-origin fraction. We show that major cancer risk factors, including age, smoking and obesity-associated inflammation, increase the mitotic age of relevant normal tissues. StemTOC correlates with a somatic mutational clock-like signature, yet data indicates that the former is a more sensitive proxy for mitotic age. These results support the view that DNAm can track mitotic age in the tumor cell of origin of normal, preneoplastic and cancer tissues. StemTOC is freely available and could be adapted for future cancer-risk prediction strategies.