Epigenetic Biomarkers

Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA, .
Current topics in microbiology and immunology (Impact Factor: 3.47). 08/2011; 355. DOI: 10.1007/82_2011_165
Source: PubMed

ABSTRACT Profound changes in the epigenetic landscape of cancer cells underlie the development of human malignancies. These changes include large-scale DNA methylation changes throughout the genome as well as alterations in the compendium of post-translational chromatin modifications. Epigenetic aberrations impact multiple steps during tumorigenesis, ultimately promoting the selection of neoplastic cells with increasing pathogenicity. Identification of these alterations for use as predictive and prognostic biomarkers has been a highly sought after goal. Recent advances in the field have not only greatly expanded our knowledge of the epigenetic changes driving neoplasia but also demonstrated their significant clinical utility as cancer biomarkers. These biomarkers have proved to be useful for identifying patients whose malignancies are sensitive to specific cytotoxic chemotherapies and may hold promise for predicting which patients will benefit from newer targeted agents directed at oncogenes. The recent application of global analysis strategies has further accelerated our understanding of the epigenome and promises to enhance the identification of epigenomic programs underlying cancer progression and treatment response.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The G-protein-coupled bile acid receptor Gpbar1 (TGR5) has been demonstrated to be able to negatively regulate hepatic inflammatory response. In this study, we aimed to determine the methylation status of TGR5 promoter in patients with acute-on-chronic hepatitis B liver failure (ACHBLF) and its predictive value for prognosis. We enrolled 76 consecutive ACHBLF patients, 80 chronic hepatitis B (CHB) patients and 30 healthy controls (HCs). Methylation status of TGR5 promoter in peripheral mononuclear cell (PBMC) was detected by methylation-specific polymerase chain reaction (MSP). The mRNA level of TGR5 was determined by quantitative real-time polymerase chain reaction (RT-qPCR). We found that the frequency of TGR5 promoter methylation was significantly higher in ACHBLF (35/76, 46.05%) than CHB patients (5/80, 6.25%; χ(2) = 32.38, P < 0.01) and HCs (1/30, 3.33%; χ(2) = 17.50, P < 0.01). TGR5 mRNA level was significantly lower (Z = -9.12, P < 0.01) in participants with aberrant methylation than those without. TGR5 methylation showed a sensitivity of 46.05% (35/76), specificity of 93.75% (75/80), positive predictive value (PPV) of 87.5% (35/40) and negative predictive value (NPV) of 64.66% (75/116) in discriminating ACHBLF from CHB patients. ACHBLF patients with methylated TGR5 showed significantly poor survival than those without (P < 0.01). When used to predict 3-month mortality of ACHBLF, TGR5 methylation [area under the receiver operating characteristic curve (AUC) = 0.75] performed significantly better than model for end-stage liver diseases (MELD) score (AUC = 0.65; P < 0.05). Therefore, our study demonstrated that aberrant TGR5 promoter methylation occurred in ACHBLF and might be a potential prognostic marker for the disease.
    Journal of Viral Hepatitis 07/2014; 22(2). DOI:10.1111/jvh.12277 · 3.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a newly identified liver tumor suppressor in carcinogenesis. This present study was therefore to determine the potential value of serum TGR5 promoter methylation in identifying hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) patients. Methods: The circulating cell-free DNA (cfDNA) was extracted from a retrospective dataset including 160 HCC, 88 CHB and 45 healthy controls (HCs). Methylation status of TGR5 promoter was examined by methylation-specific polymerase chain reaction (MSP). Results: Hypermethylation of the TGR5 promoter occurred significantly more frequent in HCC (77/160, 48.13%) than CHB (12/88, 13.64%; p<0.01) and HCs (2/45, 4.44%; p<0.01). The methylation rate of TGR5 in HCC patients ≥60 years old was significantly higher than those <60 years old (p<0.05). Alpha fetoprotein (AFP) had sensitivity of 58.13%, 30.63% and 24.38% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had sensitivity of 81.25%, 68.13% and 65%. AFP had specificity of 47.73%, 92.05% and 98.86% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had specificity of 38.64%, 78.41% and 85.23%. AFP had Youden index of 0.06, 0.23 and 0.23 at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had Youden index of 0.20, 0.47 and 0.50. Conclusions: Our findings strongly suggested the combination of serum TGR5 promoter methylation and AFP enhanced the diagnostic value of AFP alone in discriminating HCC from CHB patients.
    International journal of medical sciences 01/2014; 11(2):164-71. DOI:10.7150/ijms.6745 · 1.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic therapy reverting aberrant acetylation or methylation offers the possibility to target preferentially tumor cells and to preserve normal cells. Combination epigenetic therapy may further improve the effect of individual drugs. We investigated combined action of demethylating agent decitabine and histone deacetylase inhibitor SAHA (Vorinostat) on different leukemic cell lines in comparison with peripheral blood lymphocytes. Large decrease of viability, as well as huge p21WAF1 induction, reactive oxygen species formation, and apoptotic features due to combined decitabine and SAHA action were detected in leukemic cell lines irrespective of their p53 status, while essentially no effect was observed in response to the combined drug action in normal peripheral blood lymphocytes of healthy donors. p53-dependent apoptotic pathway was demonstrated to participate in the wtp53 CML-T1 leukemic cell line response, while significant influence of reactive oxygen species on viability decrease has been detected in p53-null HL-60 cell line.
    08/2013; 2013:659254. DOI:10.1155/2013/659254