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Implications of Epigenetic Drift in Colorectal Neoplasia
- Source :
- Cancer research. 79(3)
- Publication Year :
- 2018
-
Abstract
- Many normal tissues undergo age-related drift in DNA methylation, providing a quantitative measure of tissue age. Here, we identify and validate 781 CpG islands (CGI) that undergo significant methylomic drift in 232 normal colorectal tissues and show that these CGI continue to drift in neoplasia while retaining significant correlations across samples. However, compared with normal colon, this drift advanced (∼3–4-fold) faster in neoplasia, consistent with increased cell proliferation during neoplastic progression. The observed drift patterns were broadly consistent with modeled adenoma-to-carcinoma sojourn time distributions from colorectal cancer incidence data. These results support the hypothesis that, beginning with the founder premalignant cell, cancer precursors frequently sojourn for decades before turning into cancer, implying that the founder cell typically arises early in life. At least 77% to 89% of the observed drift variance in distal and rectal tumors was explained by stochastic variability associated with neoplastic progression, whereas only 55% of the variance was explained for proximal tumors. However, gene–CGI pairs in the proximal colon that underwent drift were significantly and primarily negatively correlated with cancer gene expression, suggesting that methylomic drift participates in the clonal evolution of colorectal cancer. Methylomic drift advanced in colorectal neoplasia, consistent with extended sojourn time distributions, which accounts for a significant fraction of epigenetic heterogeneity in colorectal cancer. Importantly, these estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing colorectal cancer incidence. Significance: These findings present age-related methylomic drift in colorectal neoplasia as evidence that premalignant cells can persist for decades before becoming cancerous. See related commentary by Sapienza, p. 437
- Subjects :
- 0301 basic medicine
Oncology
Adult
Cancer Research
medicine.medical_specialty
Colorectal cancer
Gene Expression
Biology
Somatic evolution in cancer
Epigenesis, Genetic
03 medical and health sciences
Young Adult
0302 clinical medicine
Internal medicine
medicine
Humans
Epigenetics
Young adult
Premalignant Cell
Aged
Aged, 80 and over
Stochastic Processes
Models, Genetic
Age Factors
Cancer
DNA Methylation
Middle Aged
medicine.disease
030104 developmental biology
CpG site
030220 oncology & carcinogenesis
DNA methylation
CpG Islands
Colorectal Neoplasms
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 79
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....e3e774b8aab794c78e46ed454820a615