Dataset Information

Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma.

ABSTRACT: The impact of folate deficiency on global DNA methylation is uncertain. It also is unclear whether global DNA methylation is associated with outcome in HCC. LINE-1 methylation levels, as a surrogate marker of global methylation, may be influenced by folate deficiency. However, the interaction between LINE-1 methylation and folate level on overall survival (OS) in hepatocellular carcinoma (HCC) patients is unknown. We evaluated whether LINE-1 hypomethylation and folate deficiency are associated with HCC prognosis.We prospectively recruited 172 HCC patients between 2008 and 2012. LINE-1 methylation levels in plasma and white blood cells (WBC) were measured by pyrosequencing, and plasma folate levels by a radioprotein-binding assay.Patients with plasma LINE-1 methylation <70.0% (hypomethylation) had significantly worse OS compared with those with ?70.0% methylation (hypermethylation) [hazard ratio (HR) = 1.77; 95% confidence interval (CI) 1.12-2.79; P = 0.015]. HCC patients with lower plasma folate levels also had worse survival (<27.7 vs. ?27.7 nmol/L; HR = 1.96; 95% CI, 1.24-3.09; P = 0.004). Furthermore, survival was poor in patients in whom both plasma LINE-1 methylation and folate levels were low compared with those patients in whom both levels were high (HR = 3.36; 95%CI, 1.77-6.40; P < 0.001). This interaction neared statistical significance (P = 0.057). No significant association was found between WBC LINE-1 methylation levels and survival.These findings suggest that both lower plasma levels of LINE-1 methylation and folate are associated with worse survival in HCC patients.

SUBMITTER: Yeh CC

PROVIDER: S-EPMC5801698 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma.

Yeh Chih-Ching CC Goyal Abhishek A Shen Jing J Wu Hui-Chen HC Strauss Joshua A JA Wang Qiao Q Gurvich Irina I Safyan Rachael A RA Manji Gulam A GA Gamble Mary V MV Siegel Abby B AB Santella Regina M RM

Annals of surgical oncology 20170607 12

<h4>Background</h4>The impact of folate deficiency on global DNA methylation is uncertain. It also is unclear whether global DNA methylation is associated with outcome in HCC. LINE-1 methylation levels, as a surrogate marker of global methylation, may be influenced by folate deficiency. However, the interaction between LINE-1 methylation and folate level on overall survival (OS) in hepatocellular carcinoma (HCC) patients is unknown. We evaluated whether LINE-1 hypomethylation and folate deficien ...[more]

PMID: 28593503

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Project description:Background: Hepatocellular carcinoma (HCC) is the most frequent fatal malignancy, and it has a poor prognosis. Apolipoprotein 1 (APOA-1), the main protein component of high-density lipoproteins, is involved in numerous biological processes. Thus, this study was performed to detect the clinical significance of APOA-1 mRNA, APOA-1 expression, and APOA-1DNA methylation in patients with HCC. Methods: Data mining was performed using clinical and survival data from the Cancer Genome Atlas (TCGA) and Oncomine databases. The serum concentration of APOA-1 was measured in 316 patients with HCC and 100 healthy individuals at Renmin Hospital of Wuhan University, and the intact clinical information was reviewed and determined using univariate and multivariate Cox hazard models. Results: Bioinformatic analysis revealed that APOA-1 mRNA was present at lower levels in the serum of patients with HCC than in that of healthy individuals, and there was a strong negative correlation between levels of APOA-1 mRNA and APOA-1 DNA methylation. High expression of APOA-1 transcription correlated with better overall survival (p = 0.003), and APOA-1 hypermethylation correlated with progress-free survival (p = 0.045) in HCC sufferers. Next, the clinical data analysis demonstrated that APOA-1 protein levels in the serum were significantly lower in patients with HCC than in healthy controls. Furthermore, the expression of APOA-1 was significantly associated with some significant clinical indexes, and elevated APOA-1 expression was significantly associated with favorable (OS; HR:1.693, 95% CI: 1.194-2.401, p = 0.003) and better progression-free survival (PFS; HR = 1.33, 95% CI = 1.194-2.401, p = 0.045). Finally, enrichment analysis suggested that co-expressed genes of APOA-1 were involved in lipoprotein metabolism and FOXA2/3 transcription factor networks. Conclusion: APOA-1 mRNA expression is negatively regulated by DNA methylation in HCC. Low expression of APOA-1 might be a potential risk biomarker to predict survival in patients with HCC.

Project description:Background: DNA damage repair (DDR) is an important mechanism for the occurrence and development of hepatocellular carcinoma (HCC), but its impact on prognosis has not been fully understood. Materials and methods: A total of 904 HCC patients were included in our study, TCGA (n = 370) and GSE14520 (n = 239) were merged into a large-sample training cohort (n = 609). The training cohort was clustered into C1 and C2 based on prognostic DDR-related genes, the differentially expressed genes (DEGs) between C1 and C2 were identified by the Wilcoxon signed-rank test referred to criteria (|log2FC|≥1 and FDR< 0.05). The univariate Cox analysis was used to screen the prognostic-related DEGs, and Lasso penalized Cox regression analysis was used to construct the risk score. The patients were clarified into high- and low-risk groups based on the median risk score. ICGC (n = 231) and GSE116174 (n = 64) cohorts were used for external validation of the risk score's prognostic value. Results: The Kaplan-Meier survival analysis showed that the high-risk group had a significantly reduced overall survival (OS) compared to the low-risk group in the three independent cohorts, and the time-dependent ROC curve showed that the five-gene (STMN1, PON1, PLOD2, MARCKSL1, and SPP1) risk score with a high accuracy in predicting OS. The patients with AFP >300 ng/ml, tumor poor differentiation (grade 3-4), micro and macro vascular tumor invasion, advanced stage (AJCC III-IV, BCLC stage B-C, and CLIP score >2) exhibited a higher risk score. Subgroup survival analysis found that the risk score was applicable to patients with different clinical characteristics. GO and KEGG functional enrichment analysis revealed that cell cycle, p53 signaling, TNF signaling-related pathways were upregulated in the high-risk group. The higher infiltration level of activated CD4 T cell, CD56 bright natural killer cell, plasmacytoid dendritic cell, and type 2 T helper cells were found to lead an unfavorable impact on the OS of HCC patients, and these four kinds of immune cells exhibited a higher infiltration level in the high-risk group. Conclusion: The five-gene risk score proposed in the research may provide new insights into the individualized evaluation of HCC prognosis.

Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is a common cancer characterized by late diagnosis and poor prognosis. The aim of this study was to identify a novel ferroptosis-related DNA methylation signature as an alternative diagnosis index for patients with HNSCC.MethodsMethylome and transcriptome data of 499 HNSCC patients, including 275 oral squamous cell carcinoma (OSCC) samples, were obtained from The Cancer Genome Atlas (TCGA). An additional independent methylation dataset of 50 OSCC patients from the NCBI Gene Expression Omnibus (GEO) database was used for validation. As an index of ferroptosis activity, the ferroptosis score (FS) of each patient was inferred from the transcriptome data using single-sample gene set enrichment analysis. Univariate, multivariate, and LASSO Cox regression analyses were used to select CpG sites for the construction of a ferroptosis-related DNA methylation signature for diagnosis of patients.ResultsWe initially inferred the FS of each TCGA HNSCC patient and divided the samples into high- and low-FS subgroups. Results showed that the high-FS subgroup displayed poor overall survival. Moreover, 378 differentially methylated CpG sites (DMCs) were identified between the two HNSCC subgroups, with 16 selected to construct a 16-DNA methylation signature for risk prediction in HNSCC patients using the LASSO and multivariate Cox regression models. Relative operating characteristic (ROC) curve analysis showed great predictive efficiency for 1-, 3-, and 5-year HNSCC survival using the 16-DNA methylation signature. Its predictive efficiency was also observed in OSCC patients from the TCGA and GEO databases. In addition, we found that the signature was associated with the fractions of immune types in the tumor immune microenvironment (TIME), suggesting potential interactions between ferroptosis and TIME in HNSCC progression.ConclusionsWe established a novel ferroptosis-related 16-DNA methylation signature that could be applied as an alternative tool to predict prognosis outcome in patients with HNSCC, including OSCC.

Dataset Information

Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma.

Publications

Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma.

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