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Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome

The human genome is organized into topologically associating domains (TADs), which represent contiguous regions with a higher frequency of intra-interactions as opposed to inter-interactions. TADs contribute to gene expression regulation by restricting the interactions between their regulatory eleme...

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Detalles Bibliográficos
Autores principales: Li, Lifei, Barth, Nicolai K. H., Pilarsky, Christian, Taher, Leila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966451/
https://www.ncbi.nlm.nih.gov/pubmed/31783642
http://dx.doi.org/10.3390/cancers11121886
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author Li, Lifei
Barth, Nicolai K. H.
Pilarsky, Christian
Taher, Leila
author_facet Li, Lifei
Barth, Nicolai K. H.
Pilarsky, Christian
Taher, Leila
author_sort Li, Lifei
collection PubMed
description The human genome is organized into topologically associating domains (TADs), which represent contiguous regions with a higher frequency of intra-interactions as opposed to inter-interactions. TADs contribute to gene expression regulation by restricting the interactions between their regulatory elements, and TAD disruption has been associated with cancer. Here, we provide a proof of principle that mutations within TADs can be used to predict the survival of cancer patients. Specifically, we constructed a set of 1467 consensus TADs representing the three-dimensional organization of the human genome and used Cox regression analysis to identify a total of 35 prognostic TADs in different cancer types. Interestingly, only 46% of the 35 prognostic TADs comprised genes with known clinical relevance. Moreover, in the vast majority of such cases, the prognostic value of the TAD was not directly related to the presence/absence of mutations in the gene(s), emphasizing the importance of regulatory mutations. In addition, we found that 34% of the prognostic TADs show strong structural perturbations in the cancer genome, consistent with the widespread, global epigenetic dysregulation often observed in cancer patients. In summary, this study elucidates the mechanisms through which non-coding variants may influence cancer progression and opens new avenues for personalized medicine.
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spelling pubmed-69664512020-01-27 Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome Li, Lifei Barth, Nicolai K. H. Pilarsky, Christian Taher, Leila Cancers (Basel) Article The human genome is organized into topologically associating domains (TADs), which represent contiguous regions with a higher frequency of intra-interactions as opposed to inter-interactions. TADs contribute to gene expression regulation by restricting the interactions between their regulatory elements, and TAD disruption has been associated with cancer. Here, we provide a proof of principle that mutations within TADs can be used to predict the survival of cancer patients. Specifically, we constructed a set of 1467 consensus TADs representing the three-dimensional organization of the human genome and used Cox regression analysis to identify a total of 35 prognostic TADs in different cancer types. Interestingly, only 46% of the 35 prognostic TADs comprised genes with known clinical relevance. Moreover, in the vast majority of such cases, the prognostic value of the TAD was not directly related to the presence/absence of mutations in the gene(s), emphasizing the importance of regulatory mutations. In addition, we found that 34% of the prognostic TADs show strong structural perturbations in the cancer genome, consistent with the widespread, global epigenetic dysregulation often observed in cancer patients. In summary, this study elucidates the mechanisms through which non-coding variants may influence cancer progression and opens new avenues for personalized medicine. MDPI 2019-11-27 /pmc/articles/PMC6966451/ /pubmed/31783642 http://dx.doi.org/10.3390/cancers11121886 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Lifei
Barth, Nicolai K. H.
Pilarsky, Christian
Taher, Leila
Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome
title Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome
title_full Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome
title_fullStr Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome
title_full_unstemmed Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome
title_short Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome
title_sort cancer is associated with alterations in the three-dimensional organization of the genome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966451/
https://www.ncbi.nlm.nih.gov/pubmed/31783642
http://dx.doi.org/10.3390/cancers11121886
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