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Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains

Cancer is characterized by both genetic and epigenetic alterations. While cancer driver mutations and copy-number alterations have been studied at a systems-level, relatively little is known about the systems-level patterns exhibited by their epigenetic counterparts. Here we perform a pan-cancer wid...

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Autores principales: Gao, Yang, Teschendorff, Andrew E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314760/
https://www.ncbi.nlm.nih.gov/pubmed/27899617
http://dx.doi.org/10.1093/nar/gkw1100
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author Gao, Yang
Teschendorff, Andrew E.
author_facet Gao, Yang
Teschendorff, Andrew E.
author_sort Gao, Yang
collection PubMed
description Cancer is characterized by both genetic and epigenetic alterations. While cancer driver mutations and copy-number alterations have been studied at a systems-level, relatively little is known about the systems-level patterns exhibited by their epigenetic counterparts. Here we perform a pan-cancer wide systems-level analysis, mapping candidate cancer-driver DNA methylation (DNAm) alterations onto a human interactome. We demonstrate that functional DNAm alterations in cancer tend to map to nodes of lower connectivity and inter-connectivity, compared to the corresponding alterations at the genomic level. We find that epigenetic alterations are relatively over-represented in extracellular and transmembrane signaling domains, whereas cancer genes undergoing amplification or deletion tend to be enriched within the intracellular domain. A pan-cancer wide meta-analysis identifies WNT and chemokine signaling, as two key pathways where epigenetic deregulation preferentially targets extracellular components. We further pinpoint specific chemokine ligands/receptors whose epigenetic deregulation associates with key epigenetic enzymes, representing potential targets for epigenetic therapy. Our results suggest that epigenetic deregulation in cancer not only targets tissue-specific transcription factors, but also modulates signaling within the extra-cellular domain, providing novel system-level insight into the potential distinctive role of genetic and epigenetic alterations in cancer.
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spelling pubmed-53147602017-02-21 Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains Gao, Yang Teschendorff, Andrew E. Nucleic Acids Res Computational Biology Cancer is characterized by both genetic and epigenetic alterations. While cancer driver mutations and copy-number alterations have been studied at a systems-level, relatively little is known about the systems-level patterns exhibited by their epigenetic counterparts. Here we perform a pan-cancer wide systems-level analysis, mapping candidate cancer-driver DNA methylation (DNAm) alterations onto a human interactome. We demonstrate that functional DNAm alterations in cancer tend to map to nodes of lower connectivity and inter-connectivity, compared to the corresponding alterations at the genomic level. We find that epigenetic alterations are relatively over-represented in extracellular and transmembrane signaling domains, whereas cancer genes undergoing amplification or deletion tend to be enriched within the intracellular domain. A pan-cancer wide meta-analysis identifies WNT and chemokine signaling, as two key pathways where epigenetic deregulation preferentially targets extracellular components. We further pinpoint specific chemokine ligands/receptors whose epigenetic deregulation associates with key epigenetic enzymes, representing potential targets for epigenetic therapy. Our results suggest that epigenetic deregulation in cancer not only targets tissue-specific transcription factors, but also modulates signaling within the extra-cellular domain, providing novel system-level insight into the potential distinctive role of genetic and epigenetic alterations in cancer. Oxford University Press 2017-01-25 2016-11-28 /pmc/articles/PMC5314760/ /pubmed/27899617 http://dx.doi.org/10.1093/nar/gkw1100 Text en © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Computational Biology
Gao, Yang
Teschendorff, Andrew E.
Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains
title Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains
title_full Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains
title_fullStr Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains
title_full_unstemmed Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains
title_short Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains
title_sort epigenetic and genetic deregulation in cancer target distinct signaling pathway domains
topic Computational Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314760/
https://www.ncbi.nlm.nih.gov/pubmed/27899617
http://dx.doi.org/10.1093/nar/gkw1100
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