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Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations

Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors....

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Detalles Bibliográficos
Autores principales: Thompson, Jeffrey A., Christensen, Brock C., Marsit, Carmen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121907/
https://www.ncbi.nlm.nih.gov/pubmed/30081598
http://dx.doi.org/10.3390/ijms19082296
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author Thompson, Jeffrey A.
Christensen, Brock C.
Marsit, Carmen J.
author_facet Thompson, Jeffrey A.
Christensen, Brock C.
Marsit, Carmen J.
author_sort Thompson, Jeffrey A.
collection PubMed
description Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors. We tested this hypothesis using data from genome-scale DNA methylation (14 cancer types), simple somatic mutation (10 cancer types), and copy number variation profiling (14 cancer types). For DNA methylation, the difference in rank differential methylation between tumor and tumor-adjacent normal matched samples based on promoter type was tested by the Wilcoxon rank sum test. Logistic regression was used to compare differences in simple somatic mutations. For copy number alteration, a mixed effects logistic regression model was used. The change in methylation between non-diseased tissues and their tumor counterparts was significantly greater in single compared to bidirectional promoters across all 14 cancer types examined. Similarly, the extent of copy number alteration was greater in single gene compared to bidirectional promoters for all 14 cancer types. Furthermore, among 10 cancer types with available simple somatic mutation data, bidirectional promoters were slightly more susceptible. These results suggest that selective pressures related with specific functional impacts during carcinogenesis drive the susceptibility of promoter regions to somatic alteration.
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spelling pubmed-61219072018-09-07 Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations Thompson, Jeffrey A. Christensen, Brock C. Marsit, Carmen J. Int J Mol Sci Article Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors. We tested this hypothesis using data from genome-scale DNA methylation (14 cancer types), simple somatic mutation (10 cancer types), and copy number variation profiling (14 cancer types). For DNA methylation, the difference in rank differential methylation between tumor and tumor-adjacent normal matched samples based on promoter type was tested by the Wilcoxon rank sum test. Logistic regression was used to compare differences in simple somatic mutations. For copy number alteration, a mixed effects logistic regression model was used. The change in methylation between non-diseased tissues and their tumor counterparts was significantly greater in single compared to bidirectional promoters across all 14 cancer types examined. Similarly, the extent of copy number alteration was greater in single gene compared to bidirectional promoters for all 14 cancer types. Furthermore, among 10 cancer types with available simple somatic mutation data, bidirectional promoters were slightly more susceptible. These results suggest that selective pressures related with specific functional impacts during carcinogenesis drive the susceptibility of promoter regions to somatic alteration. MDPI 2018-08-05 /pmc/articles/PMC6121907/ /pubmed/30081598 http://dx.doi.org/10.3390/ijms19082296 Text en © 2018 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
Thompson, Jeffrey A.
Christensen, Brock C.
Marsit, Carmen J.
Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations
title Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations
title_full Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations
title_fullStr Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations
title_full_unstemmed Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations
title_short Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations
title_sort pan-cancer analysis reveals differential susceptibility of bidirectional gene promoters to dna methylation, somatic mutations, and copy number alterations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121907/
https://www.ncbi.nlm.nih.gov/pubmed/30081598
http://dx.doi.org/10.3390/ijms19082296
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