Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome

Aging is the leading risk factor for cancer. While it’s been proposed that the age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. Here, we show that both aging and cancer share a common epigenetic replication signature, which we modeled from DNA methylation data in extensively passaged immortalized human cells in vitro and tested on clinical tissues. This epigenetic signature of replication – termed CellDRIFT – increased with age across multiple tissues, distinguished tumor from normal tissue, and was escalated in normal breast tissue from cancer patients. Additionally, within-person tissue differences were correlated with both predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Overall, our findings suggest that age-related replication drives epigenetic changes in cells, pushing them towards a more tumorigenic state. One sentence summary Cellular replication leaves an epigenetic fingerprint that may partially underly the age-associated increase in cancer risk. ### Competing Interest Statement The authors have declared no competing interest.