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

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 princip...

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Autores principales: Ryser, Marc D., Yu, Ming, Grady, William, Siegmund, Kimberly, Shibata, Darryl
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251922/
https://www.ncbi.nlm.nih.gov/pubmed/30470817
http://dx.doi.org/10.1038/s41598-018-35621-y
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author Ryser, Marc D.
Yu, Ming
Grady, William
Siegmund, Kimberly
Shibata, Darryl
author_facet Ryser, Marc D.
Yu, Ming
Grady, William
Siegmund, Kimberly
Shibata, Darryl
author_sort Ryser, Marc D.
collection PubMed
description 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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spelling pubmed-62519222018-11-30 Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance Ryser, Marc D. Yu, Ming Grady, William Siegmund, Kimberly Shibata, Darryl Sci Rep Article 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. Nature Publishing Group UK 2018-11-23 /pmc/articles/PMC6251922/ /pubmed/30470817 http://dx.doi.org/10.1038/s41598-018-35621-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ryser, Marc D.
Yu, Ming
Grady, William
Siegmund, Kimberly
Shibata, Darryl
Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance
title Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance
title_full Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance
title_fullStr Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance
title_full_unstemmed Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance
title_short Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance
title_sort epigenetic heterogeneity in human colorectal tumors reveals preferential conservation and evidence of immune surveillance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251922/
https://www.ncbi.nlm.nih.gov/pubmed/30470817
http://dx.doi.org/10.1038/s41598-018-35621-y
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