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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.

2022-09-17 cancer biology
10.1101/2022.09.14.507975 bioRxiv
Show 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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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.