PT  - JOURNAL ARTICLE
AU  - Christopher J. Minteer
AU  - Kyra Thrush
AU  - Peter Niimi
AU  - Joel Rozowsky
AU  - Jason Liu
AU  - Mor Frank
AU  - Thomas McCabe
AU  - Erin Hofstatter
AU  - Mariya Rozenblit
AU  - Lajos Pusztai
AU  - Kenneth Beckman
AU  - Mark Gerstein
AU  - Morgan E. Levine
TI  - Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome
AID  - 10.1101/2022.09.14.507975
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.09.14.507975
4099  - http://biorxiv.org/content/early/2022/09/17/2022.09.14.507975.short
4100  - http://biorxiv.org/content/early/2022/09/17/2022.09.14.507975.full
AB  - 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 StatementThe authors have declared no competing interest.