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Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, accounting for an estimated 600,000 deaths annually. Aberrant methylation, consisting of DNA hypomethylation and/or promoter gene CpG hypermethylation, is implicated in the development of a variety of solid tumors, including HCC. We analyzed the global levels of DNA methylation as well as the methylation status of 105 putative tumor suppressor genes and found that the extent of genome-wide hypomethylation and CpG hypermethylation correlates with biological features and clinical outcome of HCC patients. We identified activation of Ras and downstream Ras effectors (ERK, AKT, and RAL) due to epigenetic silencing of inhibitors of the Ras pathway in all HCC. Further, selective inactivation of SPRY1 and -2, DAB2, and SOCS4 and -5 genes and inhibitors of angiogenesis (BNIP3, BNIP3L, IGFBP3, and EGLN2) was associated with poor prognosis. Importantly, several epigenetically silenced putative tumor suppressor genes found in HCC were also inactivated in the nontumorous liver. Our results assign both therapeutic and chemopreventive significance to methylation patterns in human HCC and open the possibility of using molecular targets, including those identified in this study, to effectively inhibit HCC development and progression.

SUBMITTER: Calvisi DF

PROVIDER: S-EPMC1950459 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma.

Calvisi Diego F DF Ladu Sara S Gorden Alexis A Farina Miriam M Lee Ju-Seog JS Conner Elizabeth A EA Schroeder Insa I Factor Valentina M VM Thorgeirsson Snorri S SS

The Journal of clinical investigation 20070901 9

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, accounting for an estimated 600,000 deaths annually. Aberrant methylation, consisting of DNA hypomethylation and/or promoter gene CpG hypermethylation, is implicated in the development of a variety of solid tumors, including HCC. We analyzed the global levels of DNA methylation as well as the methylation status of 105 putative tumor suppressor genes and found that the extent of genome-wide hypomethylation and CpG hypermeth ...[more]

PMID: 17717605

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Project description:Background: Hepatocellular carcinoma (HCC) is a tumor with high morbidity and high mortality worldwide. DNA methylation, one of the most common epigenetic changes, might serve a vital regulatory role in cancer. Methods: To identify categories based on DNA methylation data, consensus clustering was employed. The risk signature was yielded by systematic bioinformatics analyses based on the remarkably methylated CpG sites of cluster 1. Kaplan-Meier analysis, variable regression analysis, and ROC curve analysis were further conducted to validate the prognosis predictive ability of risk signature. Gene set enrichment analysis (GSEA) was performed for functional annotation. To uncover the context of tumor immune microenvironment (TIME) of HCC, we employed the ssGSEA algorithm and CIBERSORT method and performed TIMER database exploration and single-cell RNA sequencing analysis. Additionally, quantitative real-time polymerase chain reaction was employed to determine the LRRC41 expression and preliminarily explore the latent role of LRRC41 in prognostic prediction. Finally, mutation data were analyzed by employing the "maftools" package to delineate the tumor mutation burden (TMB). Results: HCC samples were assigned into seven subtypes with different overall survival and methylation levels based on 5'-cytosine-phosphate-guanine-3' (CpG) sites. The risk prognostic signature including two candidate genes (LRRC41 and KIAA1429) exhibited robust prognostic predictive accuracy, which was validated in the external testing cohort. Then, the risk score was significantly correlated with the TIME and immune checkpoint blockade (ICB)-related genes. Besides, a prognostic nomogram based on the risk score and clinical stage presented powerful prognostic ability. Additionally, LRRC41 with prognostic value was corroborated to be closely associated with TIME characterization in both expression and methylation levels. Subsequently, the correlation regulatory network uncovered the potential targets of LRRC41 and KIAA1429. Finally, the methylation level of KIAA1429 was correlated with gene mutation status. Conclusion: In summary, this is the first to identify HCC samples into distinct clusters according to DNA methylation and yield the CpG-based prognostic signature and quantitative nomogram to precisely predict prognosis. And the pivotal player of DNA methylation of genes in the TIME and TMB status was explored, contributing to clinical decision-making and personalized prognosis monitoring of HCC.

Project description:BackgroundBy the time they are clinically diagnosed, patients with hepatocellular carcinoma (HCC) are often at the advanced stage. DNA methylation has become a useful predictor of prognosis for cancer patients. Research on DNA methylation as a biomarker for assessing the risk of occurrence in HCC patients is limited. The purpose of this study was to develop an efficient methylation site model for predicting survival in patients with HCC.MethodsDNA methylation and gene expression profile data were extracted from The Cancer Genome Atlas (TCGA) database. Markers of DNA-methylated site in two subsets (the training subset and the test subset) were identified using a random survival forest algorithm and Cox proportional hazards regression. Then, Gene Ontology annotations were applied to investigate the functions of DNA methylation signatures.ResultsA total of 37 hub genes containing 713 methylated sites were identified among the differentially methylated genes (DMGs) and differentially expressed genes (DEGs). Finally, seven methylation sites (cg12824782, cg24871714, cg18683774, cg22796509, cg19450025, cg10474350, and cg06511917) were identified. In the training group and the test group, the area under the curve predicting the survival of patients with HCC was 0.750 and 0.742, respectively. The seven methylation sites signature could be used to divide the patients in the training group into high- and low-risk subgroups [overall survival (OS): 2.81 vs. 2.11 years; log-rank test, P<0.05]. Then, the prediction ability of the model was validated in the test dataset through risk stratification (OS: 2.04 vs. 2.88 years; log-rank test, P<0.05). Functional analysis demonstrated that these signature genes were related to the activity of DNA-binding transcription activator, RNA polymerase II distal enhancer sequence-specific DNA binding, and enhancer sequence-specific DNA binding.ConclusionsThe results of this study showed that the signature is useful for predicting the survival of HCC patients and thus, can facilitate treatment-related decision-making.

Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC.Methods and findingsWe performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p=1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list.ConclusionSubstantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and prognosis.

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Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma.

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Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma.

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