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Open AccessArticle

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

1
Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS 66160, USA
2
Department of Epidemiology; Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA
3
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA
4
Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA
5
Department of Environmental Health, Rollins School of Public Health at Emory University, Atlanta, GA 30322, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(8), 2296; https://doi.org/10.3390/ijms19082296
Received: 5 July 2018 / Revised: 26 July 2018 / Accepted: 2 August 2018 / Published: 5 August 2018
(This article belongs to the Special Issue Cancer Epigenetics 2018)
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. View Full-Text
Keywords: pan-cancer; bidirectional promoters; head-to-head genes pan-cancer; bidirectional promoters; head-to-head genes
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Thompson, J.A.; Christensen, B.C.; Marsit, C.J. Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations. Int. J. Mol. Sci. 2018, 19, 2296.

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