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

Minteer, C. J.; Thrush, K.; Niimi, P.; Rozowsky, J.; Liu, J.; Frank, M.; McCabe, T.; Hofstatter, E.; Rozenblit, M.; Pusztai, L.; Beckman, K.; Gerstein, M.; Levine, M. E.

doi:10.1101/2022.09.14.507975

bioRxiv · 10.1101/2022.09.14.507975

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

Minteer, C. J.·Thrush, K.·Niimi, P.·Rozowsky, J.·Liu, J.·Frank, M.·McCabe, T.·Hofstatter, E.·Rozenblit, M.·Pusztai, L.·Beckman, K.·Gerstein, M.·Levine, M. E.

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Abstract

Aging is the leading risk factor for cancer. While its 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 summaryCellular replication leaves an epigenetic fingerprint that may partially underly the age-associated increase in cancer risk.

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Minteer, C. J., Thrush, K., Niimi, P., Rozowsky, J., Liu, J., Frank, M., McCabe, T., Hofstatter, E., Rozenblit, M., Pusztai, L., Beckman, K., Gerstein, M., Levine, M. E.. 2022-09-17. Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome. https://doi.org/10.1101/2022.09.14.507975

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