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Pharmacological unmasking microarray approach-based discovery of novel DNA methylation markers for hepatocellular carcinoma.

Jung N, Won JK, Kim BH, Suh KS, Jang JJ, Kang GH - J. Korean Med. Sci. (2012)

Bottom Line: Of the 239 promoter CpG island loci hypermethylated in HCC cell lines (as revealed by methylation-specific PCR), 221 loci were found to be hypermethylated in HCC or nonneoplastic liver tissues.In conclusion, we identified 221 novel DNA methylation markers for HCC.One promising prognostic marker, HIST1H2AE, should be further validated in the prognostication of HCC patients.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

ABSTRACT
DNA methylation is one of the main epigenetic mechanisms and hypermethylation of CpG islands at tumor suppressor genes switches off these genes. To find novel DNA methylation markers in hepatocellular carcinoma (HCC), we performed pharmacological unmasking (treatment with 5-aza-2'-deoxycytidine or trichostatin A) followed by microarray analysis in HCC cell lines. Of the 239 promoter CpG island loci hypermethylated in HCC cell lines (as revealed by methylation-specific PCR), 221 loci were found to be hypermethylated in HCC or nonneoplastic liver tissues. Thirty-three loci showed a 20% higher methylation frequency in tumors than in adjacent nonneoplastic tissues. Correlation of individual cancer-related methylation markers with clinicopathological features of HCC patients (n = 95) revealed that the number of hypermethylated genes in HCC tumors was higher in older than in younger patients. Univariate and multivariate survival analysis revealed that the HIST1H2AE methylation status is closely correlated with the patient's overall survival (P = 0.022 and P = 0.010, respectively). In conclusion, we identified 221 novel DNA methylation markers for HCC. One promising prognostic marker, HIST1H2AE, should be further validated in the prognostication of HCC patients.

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Kaplan-Meier survival curves of 90 hepatocellular carcinoma (HCC) patients. Correlation of (A) HIST1H2AE, and (B) EFEMP2 methylation status with overall survival.
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Figure 10: Kaplan-Meier survival curves of 90 hepatocellular carcinoma (HCC) patients. Correlation of (A) HIST1H2AE, and (B) EFEMP2 methylation status with overall survival.

Mentions: Correlation of DNA methylation markers with patient survival was analyzed in 90 patients. Five patients were excluded because of follow-up loss. Of the 33 CpG loci, HIST1H2AE and EFEMP2 exhibited an association between gene hypermethylation and poor prognosis (P = 0.022 and P = 0.081, respectively, by Kaplan-Meir log-rank test) (Fig. 10, Table 3). Among several other clinicopathological factors, tumor size, serum GGT levels, and microscopic vascular invasion showed prognostic significance. Taking into account these 3 clinicopathological factors, HIST1H2AE and EFEMP2 were included into a multivariate analysis to identify independent predictors of overall survival (Table 4). Multivariate analysis by using the COX proportional hazards model revealed that HIST1H2AE (P = 0.010) and EFEMP2 (P = 0.020) methylation status are significant variables affecting the overall survival of HCC patients. The methylation status of these two genes suggested about 2.6-fold increased risk as compared to patients who had these genes unmethylated.


Pharmacological unmasking microarray approach-based discovery of novel DNA methylation markers for hepatocellular carcinoma.

Jung N, Won JK, Kim BH, Suh KS, Jang JJ, Kang GH - J. Korean Med. Sci. (2012)

Kaplan-Meier survival curves of 90 hepatocellular carcinoma (HCC) patients. Correlation of (A) HIST1H2AE, and (B) EFEMP2 methylation status with overall survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369444&req=5

Figure 10: Kaplan-Meier survival curves of 90 hepatocellular carcinoma (HCC) patients. Correlation of (A) HIST1H2AE, and (B) EFEMP2 methylation status with overall survival.
Mentions: Correlation of DNA methylation markers with patient survival was analyzed in 90 patients. Five patients were excluded because of follow-up loss. Of the 33 CpG loci, HIST1H2AE and EFEMP2 exhibited an association between gene hypermethylation and poor prognosis (P = 0.022 and P = 0.081, respectively, by Kaplan-Meir log-rank test) (Fig. 10, Table 3). Among several other clinicopathological factors, tumor size, serum GGT levels, and microscopic vascular invasion showed prognostic significance. Taking into account these 3 clinicopathological factors, HIST1H2AE and EFEMP2 were included into a multivariate analysis to identify independent predictors of overall survival (Table 4). Multivariate analysis by using the COX proportional hazards model revealed that HIST1H2AE (P = 0.010) and EFEMP2 (P = 0.020) methylation status are significant variables affecting the overall survival of HCC patients. The methylation status of these two genes suggested about 2.6-fold increased risk as compared to patients who had these genes unmethylated.

Bottom Line: Of the 239 promoter CpG island loci hypermethylated in HCC cell lines (as revealed by methylation-specific PCR), 221 loci were found to be hypermethylated in HCC or nonneoplastic liver tissues.In conclusion, we identified 221 novel DNA methylation markers for HCC.One promising prognostic marker, HIST1H2AE, should be further validated in the prognostication of HCC patients.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

ABSTRACT
DNA methylation is one of the main epigenetic mechanisms and hypermethylation of CpG islands at tumor suppressor genes switches off these genes. To find novel DNA methylation markers in hepatocellular carcinoma (HCC), we performed pharmacological unmasking (treatment with 5-aza-2'-deoxycytidine or trichostatin A) followed by microarray analysis in HCC cell lines. Of the 239 promoter CpG island loci hypermethylated in HCC cell lines (as revealed by methylation-specific PCR), 221 loci were found to be hypermethylated in HCC or nonneoplastic liver tissues. Thirty-three loci showed a 20% higher methylation frequency in tumors than in adjacent nonneoplastic tissues. Correlation of individual cancer-related methylation markers with clinicopathological features of HCC patients (n = 95) revealed that the number of hypermethylated genes in HCC tumors was higher in older than in younger patients. Univariate and multivariate survival analysis revealed that the HIST1H2AE methylation status is closely correlated with the patient's overall survival (P = 0.022 and P = 0.010, respectively). In conclusion, we identified 221 novel DNA methylation markers for HCC. One promising prognostic marker, HIST1H2AE, should be further validated in the prognostication of HCC patients.

Show MeSH
Related in: MedlinePlus