Dataset Information

Genome-wide Analysis Reveals DNA Methylation Alterations in Obesity Associated with High Risk of Colorectal Cancer.

ABSTRACT: Obesity is a high risk factor for colorectal cancer (CRC). The contribution of underlying epigenetic mechanisms to CRC and the precise targets of epigenetic alterations during cancer development are largely unknown. Several types of epigenetic processes have been described, including DNA methylation, histone modification, and microRNA expression. To investigate the relationship between obesity and CRC, we studied both obese and CRC patients, focusing on genome-wide peripheral blood DNA methylation alterations. Our results show abnormal distributions of overlapping differentially methylated regions (DMRs) such as hypermethylated CpG islands, which may account for epigenetic instability driving cancer initiation in obesity patients. Furthermore, functional analysis suggests that altered DNA methylation of extracellular (e.g., O-glycan processing) and intracellular components contribute to activation of oncogenes (e.g. KRAS and SCL2A1) and suppression of tumor suppressors (e.g. ARHGEF4, EPHB2 and SOCS3), leading to increased oncogenic potency. Our study demonstrates how DNA methylation changes in obesity contribute to CRC development, providing direct evidence of an association between obesity and CRC. It also reveals the diagnostic potential of using DNA methylation as an early risk evaluation to detect patients with high risk for CRC.

SUBMITTER: Dong L

PROVIDER: S-EPMC6433909 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genome-wide Analysis Reveals DNA Methylation Alterations in Obesity Associated with High Risk of Colorectal Cancer.

Dong Lixin L Ma Li L Ma Gloria H GH Ren Hongmei H

Scientific reports 20190325 1

Obesity is a high risk factor for colorectal cancer (CRC). The contribution of underlying epigenetic mechanisms to CRC and the precise targets of epigenetic alterations during cancer development are largely unknown. Several types of epigenetic processes have been described, including DNA methylation, histone modification, and microRNA expression. To investigate the relationship between obesity and CRC, we studied both obese and CRC patients, focusing on genome-wide peripheral blood DNA methylati ...[more]

PMID: 30911103

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Project description:Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the United States with a five-year patient survival rate of only 6%. Early detection and treatment of this disease is hampered due to lack of reliable diagnostic and prognostic markers. Recent studies have shown that dynamic changes in the global DNA methylation and gene expression patterns play key roles in the PC development; hence, provide valuable insights for better understanding the initiation and progression of PC. In the current study, we used DNA methylation, gene expression, copy number, mutational and clinical data from pancreatic patients. We independently investigated the DNA methylation and differential gene expression profiles between normal and tumor samples and correlated methylation levels with gene expression patterns. We observed a total of ~23-thousand differentially methylated CpG sites (???0.1) between normal and tumor samples, where majority of the CpG sites are hypermethylated in PC, and this phenomenon is more prominent in the 5'UTRs and promoter regions compared to the gene bodies. Differential methylation is observed in genes associated with the homeobox domain, cell division and differentiation, cytoskeleton, epigenetic regulation and development, pancreatic development and pancreatic signaling and pancreatic cancer core signaling pathways. Correlation analysis suggests that methylation in the promoter region and 5'UTR has mostly negative correlations with gene expression while gene body and 3'UTR associated methylation has positive correlations. Regulatory element analysis suggests that HOX cluster and histone core proteins are upstream regulators of hypomethylation, while SMAD4, STAT4, STAT5B and zinc finger proteins (ZNF) are upstream regulators of hypermethylation. Non-negative matrix factorization (NMF) clustering of differentially methylated sites generated three clusters in PCs suggesting the existence of distinct molecular subtypes. Cluster 1 and cluster 2 showed samples enriched with clinical phenotypes like neoplasm histological grade and pathologic T-stage T3, respectively, while cluster 3 showed the enrichment of samples with neoplasm histological grade G1. To the best of our knowledge, this is the first genome-scale methylome analysis of PC data from TCGA. Our clustering analysis provides a strong basis for future work on the molecular subtyping of epigenetic regulation in pancreatic cancer.

Dataset Information

Genome-wide Analysis Reveals DNA Methylation Alterations in Obesity Associated with High Risk of Colorectal Cancer.

Publications

Genome-wide Analysis Reveals DNA Methylation Alterations in Obesity Associated with High Risk of Colorectal Cancer.

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