Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance
Year: 2018
Type: article
Study design: Observational Study
Abstract: 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.
Source: Scientific Reports
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Awards: The Mathematics of Breast Cancer Overtreatment: Improving Treatment Choice through Effective Communication of Personalized Cancer Risk, G1449118413, (PQ6) Radiogenomics of colorectal polyps to assess benign proliferative vs. premalignant states., G1560394926, G2141972424, Mathematical Analysis of Spatial Cancer Models, G2926448989, Arizona Cancer and Evolution Center (ACE), "Born to be Bad": Is Abnormal Cell Mobility Already Present At Initiation?, G4725523307, Mathematical Models of Cancer Evolution and HPV Infection, G740561281, G9000175310, Statistical Methods for Integrative Genomics in Cancer, Transdisciplinary Team Science in Colorectal Cancer Prognosis: the ColoCare Study, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG)
OpenAlex ID: W2901675869