In a recent study published in the Science Advances Journal, researchers reported the link between aging, cancer, and epigenomic changes.
Recent studies have reported that aging is a leading risk factor for cancer, with a higher risk among 25-65-year-olds. However, only one-third of cancers are linked to age-independent factors.
Evidence suggests that deoxyribonucleic acid (DNA) methylation is significantly altered as a direct function of cell division, and age-related epigenetic changes contribute to cancer.
Study: More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome. Image Credit: fizkes/Shutterstock.com
About the study
In the present study, researchers reported that cancer and aging are linked to replication-driven changes in the epigenome.
The team conducted a study on cancer using CellDRIFT, a tool for analyzing the replication fingerprint of immortalized astrocytes. They extracted fetal and primary astrocytes from donors. They prepared immortalized human telomerase reverse transcriptase (hTERT) astrocytes, followed by astrocyte replicative passage and cellular culturing, DNA preparation, and β-Gal and F-actin confocal microscopy.
Subsequently, the team quantified the absolute telomere length using quantitative polymerase chain reaction (qPCR), followed by computational data processing, training and validation of DNAmImmort, module clocks, CellDRIFT, and PC clocks, WGCNA module construction and hierarchical clustering, and cistrome genome ontology (GO) analysis.
A consensus network analysis was conducted to identify modules of comethylated CpGs, and the connection of 14 modules with the total number of cellular divisions (cPDs) and aging in the in vitro and in vivo settings, respectively, was studied across a wide range of tissues.
CellDRIFT was analyzed in thyroid, breast, lung, pancreas, and colon cancers, stratified by the cancer subtype. The team also analyzed histone enrichment, genetic separation, and transcription factor/chromatin controller fingerprints using each module's topmost 100 CpGs.
CellDRIFT was also tested to see if it might identify faster drift or high-risk individuals among healthy pre-diseased tissues. The team estimated CellDRIFT in samples from ENTEx, which profiled 29 tissues from four patient donors.
The team also assessed octamer-binding transcription factor 4 (OCT4), sex-determining region Y-box 2 (SOX2), Krüppel-like factor 4 (KLF4), and the master regulator of cell cycle entry and proliferative metabolism (MYC) reprogramming as well as the long-term passage among stem cells.
Time-course information was analyzed from human-origin fibroblasts programmed to produce induced pluripotent stem cells (iPSCs) and monitored by CellDRIFT during the three Yamanaka factor reprogramming phases, i.e., initiation, maturation, and stabilization.
CpG clustering was performed based on consensus clustering between the in vitro model of the present study and differently aged samples of the human liver (85 samples, 23.0 to 83.0 years old), and enrichment was assessed using the Cistrome database.
Results
The findings indicated that aging and cancer share a common epigenetic replication signature called CellDRIFT (Cellular Division and Replication Induced FingerprinT). Within-person tissue differences were correlated with predicted lifetime tissue-wise division of stem cells and cancer risk.
The replication fingerprint in DNAm accumulated with aging in multiple tissues was stronger in tumors than normal tissues, correlated with tissue-specific differences in lifetime cancer risk and total division of stem cells, and was transiently reset upon reprogramming.
The tan and yellow replication fingerprints were the most physiologically relevant, with substantial connections with age across diverse in vivo tissues such as the skin, liver, blood, and developing and adult (developed) brains.
The most interlinked tan and yellow module CpGs were enriched in the promoter core, proximal and 5' untranslated regions (5' UTR) regions, pluripotency factors, domains of cell cycle regulation, and polycomb repressive complex 2 (PRC2).
The findings indicated that many PRC2 element interactions involving upstream and downstream controllers and the core could contribute to replication-driven dysregulation. CellDRIFT from tumors was predictive of overall survival, even after adjusting for age, treatment, race, tumor grade (clinical staging), and node status (hazard ratio, 1.9).
Even after controlling for age, menopausal status, and body mass index (BMI), CellDRIFT is higher in normal tissues from individuals with breast malignancies than in those with no previous history of breast cancer.
According to the findings, individual aging variations may occur first, possibly boosting the likelihood of a random occurrence that results in "bad luck" events promoting cancer development.
CellDRIFT predicted increased epigenetic risk in healthy tissue and breast malignancy tissue and was connected with the risk of cancer and stem cell lifetime division in whole-body tissue analysis. In addition, CellDRIFT could predict patient survival.
The predicted stem cell division crossed approximately 6.0 orders of magnitude, revealing the close relationship between proliferative ability and epigenetic control.
The findings also indicated that pluripotent cells, despite having long-term passaging abilities, are not immune to replication-related epigenetic drift. The epigenetic modifications observed were similar to previous findings in aging and cancer, involving enhancers of zeste homolog 2 (EZH2) binding and chromatin accessibility regions.
Conclusion
Based on the study findings, CellDRIFT offers valuable insights into the entropic disorder associated with aging and cancer, indicating that differential epigenetic aging rates may impact individual variations in cancer risk.
Further research is required to halt or reverse these changes, and whether good lifestyle habits control luck in ways other than chance remains an urgent issue.
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