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Sci Rep. 2018 Nov 23;8(1):17292. doi: 10.1038/s41598-018-35621-y.

Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance.

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Department of Surgery, Division of Advanced Oncologic and GI Surgery, Duke University Medical Center, Durham, NC, United States.
Department of Mathematics, Duke University, Durham, NC, United States.
Department of Population Health Sciences, Duke University Medical Center, Durham, NC, United States.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States.
Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, United States.
Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, United States.


Genomic intratumoral heterogeneity (ITH) is common in cancers, but the extent of phenotypic ITH is uncertain because most subclonal mutations are passengers. Since tumor phenotypes are largely driven by epigenetics, methylomic analyses can provide insights into phenotypic ITH. Following this principle, we determined the extent of epigenetic ITH in 16 human colorectal tumors by comparing the methylomes from spatially separated regions in each tumor. Methylomes from opposite tumor sides were similar (Pearson correlation >0.95) with little evidence of ITH or stepwise selection during growth, suggesting that the epigenome of a sampled tumor largely reflects that of its founder cell. Epigenetic conservation was functional, with higher conservation at promoters and expressed genes compared to non-coding regions. Despite epigenomic conservation, RNA expression varied between individual tumor glands, indicating continued adaption during growth. Because many promoters and enhancers were unmethylated, continued adaptation may be due to phenotypic plasticity. Gene enrichment analyses identified that interferon signaling and antigen-processing and presenting pathways were strongly conserved during tumor growth, suggesting a mechanism for immune evasion. In summary, our findings suggest that epigenomes are preferentially conserved during tumor growth and that early tumor cells are poised for rapid growth, phenotypic adaptation, and immune evasion.

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