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Cancer Res. 2019 Feb 1;79(3):495-504. doi: 10.1158/0008-5472.CAN-18-1682. Epub 2018 Oct 5.

Implications of Epigenetic Drift in Colorectal Neoplasia.

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Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Centre for Tumour Biology, Barts Cancer Institute, London, United Kingdom.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington.
Molecular Diagnostics, Public Health and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington.
School of Public Health and Community Medicine, University of Washington, Seattle, Washington.
Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Department of Pathology, University of Michigan, Ann Arbor, Michigan.
Gastroenterology Section, VA Puget Sound Health Care System, Seattle, Washington.
Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou China.
Gastrointestinal Institute, Sun Yat-Sen University, Guangzhou, China.
GI Cancer Prevention Program, Seattle Cancer Care Alliance, Seattle, Washington.


: 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.

[Available on 2020-02-01]

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