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Exploring DNA Methylation Profiles Altered in Cryptogenic Hepatocellular Carcinomas by High-Throughput Targeted DNA Methylation Sequencing: A Preliminary Study for Cryptogenic Hepatocellular Carcinoma.

ABSTRACT: Background:Hepatocellular carcinoma (HCC) includes cryptogenic hepatocellular carcinomas (CR-HCC) that lack a defined cause. Specific DNA methylation patterns and comparisons of the aberrant alterations in DNA methylation between CR-HCC and adjacent peritumor tissues (APTs) have not yet been reported. Methods:The SureSelectXT Methyl-Seq Target Enrichment System was used to sequence targeted DNA methylation in three paired CR-HCC tissues and APTs. Gene Ontology (GO) enrichment and KEGG pathway analysis were performed to investigate the DNA methylation mechanism of CR-HCC. The mRNA expression levels of HOXB-AS3, HOXB6, HOXB3, USP18, MAP3K6, TIRAP, TNNI2, SHC3, CTTN, and TFAP2A, selected from the identified signaling pathways, were evaluated by quantitative real-time PCR (qPCR). Results:A total of 1728 differentially methylated regions (DMRs) were identified in tumor tissues compared with non-tumor tissues, of which 868 DMRs were hypermethylated and 860 were hypomethylated. The DMRs were mapped within 2091 DMR-associated genes (DMGs). The mRNA expression of HOXB-AS3, HOXB3, and MAP3K6 was downregulated in CR-HCC tissues compared to the APTs. However, the mRNA expression of TIRAP, SHC3, and CTTN was upregulated in the CR-HCC tissues. Differences between the mRNA expression of HOXB6, USP18, TNNI2, and TFAP2A in the CR-HCC and APTS tissues were not statistically significant. GO analysis showed that the molecular functions of "binding", "protein binding", and "cytoskeletal protein binding" were the main categories for the hypermethylated DMGs. The hypomethylated DMGs were mostly enriched in the molecular functions "binding", "protein binding", "calcium ion binding", among others. KEGG pathway analysis showed that the hypermethylated DMGs were enriched in several pathways such as "estrogen signaling pathway", while hypomethylated DMGs were enriched in several pathways such as "proteoglycans in cancer", suggesting that epigenetic modifications play important roles in the cryptogenic hepatocarcinogenesis. Conclusion:These results provide useful information for future work to characterize the functions of epigenetic mechanisms on CR-HCC.

SUBMITTER: Wang X

PROVIDER: S-EPMC7547808 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Exploring DNA Methylation Profiles Altered in Cryptogenic Hepatocellular Carcinomas by High-Throughput Targeted DNA Methylation Sequencing: A Preliminary Study for Cryptogenic Hepatocellular Carcinoma.

Wang Xin X Cheng Ya Y Yan Liang-Liang LL An Ran R Wang Xing-Yu XY Wang Heng-Yi HY

OncoTargets and therapy 20201006

<h4>Background</h4>Hepatocellular carcinoma (HCC) includes cryptogenic hepatocellular carcinomas (CR-HCC) that lack a defined cause. Specific DNA methylation patterns and comparisons of the aberrant alterations in DNA methylation between CR-HCC and adjacent peritumor tissues (APTs) have not yet been reported.<h4>Methods</h4>The SureSelectXT Methyl-Seq Target Enrichment System was used to sequence targeted DNA methylation in three paired CR-HCC tissues and APTs. Gene Ontology (GO) enrichment and ...[more]

PMID: 33116575

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Project description:Hepatocellular carcinoma (HCC) incidence has increased in the US and also has one of the fastest growing death rates of any cancer. The purpose of the current study was to discover novel genome-wide aberrant DNA methylation patterns in HCC tumors that are predominantly HCV-related. Infinium HumanMethylation 450K BeadChip arrays were used to examine genome-wide DNA methylation profiles in 66 pairs of HCC tumor and adjacent non-tumor tissues. After Bonferroni adjustment, a total of 130,512 CpG sites significantly differed in methylation level in tumor compared with non-tumor tissues, with 28,017 CpG sites hypermethylated and 102,495 hypomethylated in tumor tissues. Absolute tumor/non-tumor methylation differences ? 20% were found in 24.9% of the hypermethylated and 43.1% of the hypomethylated CpG sites; almost 10,000 CpG sites have ? 30% DNA methylation differences. Most (60.1%) significantly hypermethylated CpG sites are located in CpG islands, with 21.6% in CpG shores and 3.6% in shelves. In contrast, only a small proportion (8.2%) of significantly hypomethylated CpG sites are situated in islands, while most are found in open sea (60.2%), shore (17.3%) or shelf (14.3%) regions. A total of 2,568 significant CpG sites (2,441 hypermethylated and 127 hypomethylated) covering 589 genes are located within 684 differentially methylated regions defined as regions with at least two significant CpG sites displaying > 20% methylation differences in the same direction within 250-bp. The top 500 significant CpG sites can significantly distinguish HCC tumor from adjacent tissues with one misclassification. Within adjacent non-tumor tissues, we also identified 75 CpG sites significantly associated with gender, 228 with HCV infection, 17,207 with cirrhosis, and 56 with both HCV infection and cirrhosis after multiple comparisons adjustment. Aberrant DNA methylation profiles across the genome were identified in tumor tissues from US HCC cases that are predominantly related to HCV infection. These results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis.

Dataset Information

Exploring DNA Methylation Profiles Altered in Cryptogenic Hepatocellular Carcinomas by High-Throughput Targeted DNA Methylation Sequencing: A Preliminary Study for Cryptogenic Hepatocellular Carcinoma.

Publications

Exploring DNA Methylation Profiles Altered in Cryptogenic Hepatocellular Carcinomas by High-Throughput Targeted DNA Methylation Sequencing: A Preliminary Study for Cryptogenic Hepatocellular Carcinoma.

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