Year: 2018
Type: article
Study design: Observational Study
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
Source: Cancer Research
Institutions: Fred Hutch Cancer Center, Barts Cancer Institute, University of Washington, University of Utah, Huntsman Cancer Institute, University of Michigan, VA Puget Sound Health Care System, Sun Yat-sen University, Sixth Affiliated Hospital of Sun Yat-sen University, Seattle Cancer Care Alliance
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: Optimal screening and surveillance regimes for early diagnosis of cancer and precision medicine using mathematical modelling, Discovery and verification of novel biomarkers of colorectal cancer recurrence, (PQ6) Radiogenomics of colorectal polyps to assess benign proliferative vs. premalignant states., G1645001270, Controlling Esophageal Cancer: A Collaborative Modeling Approach, Improving Gastrointestinal Disease Outcomes in Vulnerable Populations, A Center for the Convergence of Physical Science and Cancer Biology, Circulating microRNAs as a biomarker of colorectal cancer recurrence, G4214224098, (PQC1) Accelerated biological aging and colon polyp to cancer progression, Metabolomic Strategies for Discovery and Validation of Biomarkers of Colorectal Cancer Recurrence, A Prospective Study of Colorectal Cancer: One-Carbon Metabolism and Inflammation, NSAID and COX/PG Metabolism and Colorectal Cancer, The Colon Cancer Family Registry: Seattle, Biomarkers for Reducing Mortality of Cancers of the Colon and Esophagus, Esophageal Cancer from Cells to Population: A Multiscale Approach, Molecular Determinants of Cancer Therapeutic Response, Prostaglandin Synthesis, Genetics and Colorectal Cancer, Cancer Center Support Grant, Cancer Center Support Grant, Transdisciplinary Team Science in Colorectal Cancer Prognosis: the ColoCare Study, Translational Science of Gastrointestinal Cancer Initiation and Progression
OpenAlex ID: W2894974194