CpG Island Methylator Phenotype Associated with Tumor Recurrence in Tumor-Node-Metastasis Stage I Hepatocellular Carcinoma

Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
Annals of Surgical Oncology (Impact Factor: 3.93). 07/2010; 17(7):1917-26. DOI: 10.1245/s10434-010-0921-7
Source: PubMed


CpG island methylator phenotype (CIMP), characterized by simultaneous methylation of multiple tumor suppressor genes (TSGs), has been reported to be associated with biological malignancy in many cancers. Whether CIMP is potentially predictive of clinical outcome in hepatocellular carcinoma (HCC) remains unknown.
We investigated the methylation status of ten TSGs and CIMP in 115 samples of HCC and 48 samples of corresponding nonneoplastic liver tissues using a methylation-specific polymerase chain reaction.
The methylation frequencies of the ten genes examined in HCC were 40.0% for p14 ( ARF ), 60.9% for p15 ( INK4b ), 70.4% for p16 ( INK4a ), 34.8% for p73, 70.4% for GSTP1, 64.3% for MGMT, 13.0% for hMLH1, 59.1% for RARbeta, 82.6% for SOCS-1, and 80.9% for OPCML. CIMP+ (with six or more methylated genes) was detected in 68 (59.1%) of 115 HCCs and none of 48 nonneoplastic liver tissues. On stratified univariate analysis, patients with tumor-node-metastasis (TNM) stage I HCC with CIMP+ had significantly shorter overall survival (OS) (P = 0.002) and recurrence-free survival (RFS) (P = 0.042) than those with CIMP-. Furthermore, multivariate analysis revealed CIMP+ as an independent prognostic factor for both OS [hazard ratio (HR), 12.266; P = 0.015] and RFS (HR, 2.275; P = 0.032) in TNM stage I patients.
CIMP+ may specifically define a subgroup of patients with unfavorable outcome in TNM stage I HCC. Examination of CIMP status may be useful for stratifying prognosis of patients with early-stage HCC and identifying patients who are at higher risk for recurrence.

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    • "They defined CIMP + as HCC samples with six or more such methylated genes. They showed that CIMP + patients with TNM stage I have significantly poorer recurrence-free survival (RFS) and overall survival (OS) compared to CIMP-, TNM stage I patients [99]. Wu et al. also reported similar observation, despite their definition of CIMP + differed slightly [100]. "
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    ABSTRACT: Hepatocellular Carcinoma (HCC) is one of the most common cancers in the world and it is often associated with poor prognosis. Liver transplantation and resection are two currently available curative therapies. However, most patients cannot be treated with such therapies due to late diagnosis. This underscores the urgent need to identify potential markers that ensure early diagnosis of HCC. As more evidences are suggesting that epigenetic changes contribute hepatocarcinogenesis, DNA methylation was poised as one promising biomarker. Indeed, genome wide profiling reveals that aberrant methylation is frequent event in HCC. Many studies showed that differentially methylated genes and CpG island methylator phenotype (CIMP) status in HCC were associated with clinicopathological data. Some commonly studied hypermethylated genes include P16, SOCS1, GSTP1 and CDH1. In addition, studies have also revealed that methylation markers could be detected in patient blood samples and associated with poor prognosis of the disease. Undeniably, increasing number of methylation markers are being discovered through high throughput genome wide data in recent years. Proper and systematic validation of these candidate markers in prospective cohort is required so that their actual prognostication and surveillance value could be accurately determined. It is hope that in near future, methylation marker could be translate into clinical use, where patients at risk could be diagnosed early and that the progression of disease could be more correctly assessed.
    Full-text · Article · Mar 2014
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    • "Aberrant DNA methylation of promoter CpG islands has been associated with global hypomethylation and specific loci hypermethylation, which are believed to have potential as diagnostic markers in the progression of malignant tumors. In HCC, DNA hypermethylation of candidate genes, including GSTP1 [4], RASSF1A [5], RIZ1, APC [6], SOCS1 [7], APC [8], and E-cadherin[9], has been examined using methylation sensitive polymerase chain reaction, combined bisulfite restriction analysis (COBRA), and bisulfite sequencing techniques in previous studies. With the development of genome-wide screening, the global methylation profiling of cancer has become clearer than ever before. "
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    ABSTRACT: With the development of high-throughput screening, a variety of genetic alterations has been found in hepatocellular carcinoma (HCC). Although previous studies on HCC methylation profiles have focused on liver tissue, studies using isolated hepatocytes are rare. The heterogeneity of liver composition may impact the genuine methylation status of HCC; therefore, it is important to clarify the methylation profile of hepatocytes to aid in understanding the process of tumorigenesis. The global methylation profile of single hepatocytes isolated from liver tissue of hepatitis B virus (HBV) related HCC (HBHC) was analyzed using Illumina Infinium Human Methylation27 BeadChips, and combined bisulfite restriction analysis (COBRA) and bisulfite sequencing were used to validate the 20 significant hypermethylated genes identified. In this study, we found many noteworthy differences in the genome-wide methylation profiles of single hepatocytes of HBHC. Unsupervised hierarchical clustering analysis showed that hepatocyte methylation profiles could be classified according to three cell types: hepatocytes of HCC, adjacent hepatocytes and normal hepatocytes. Among the 20 most hypermethylated genes in the hepatocytes of HBHC, 7 novel genes (WNK2, EMILIN2, TLX3, TM6SF1, TRIM58, HIST1H4Fand GRASP) were found to be hypermethylated in HBHC and hypomethylated in paired adjacent liver tissues; these findings have not been reported in previous studies on tissue samples. The genome-wide methylation profile of purified single hepatocytes of HBHC was aided in understanding the process of tumorigenesis, and a series of novel methylated genes found in this study have the potential to be biomarkers for the diagnosis and prognosis of HBHC.
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    • "Subsequently, a similar phenotype has been described for a wide range of neoplasms including tumors of the ovary [28], bladder [29], prostate [29], stomach [30], liver [31], pancreas [32], esophagus [33] and kidney [34], as well as melanoma [35], neuroblastomas [36], leukemias [37] and lymphomas [38]. In some tumor types, such as hepatocellular carcinoma, melanoma, neuroblastoma or leukemia, CIMP has been shown to be associated with disease progression or poor patient survival [35], [36], [39], [40]. In colorectal cancer, the role of CIMP in prognosis depends on the microsatellite instability screening status [41]. "
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    ABSTRACT: Abnormal DNA methylation is well established for breast cancer and contributes to its progression by silencing tumor suppressor genes. DNA methylation profiling platforms might provide an alternative approach to expression microarrays for accurate breast tumor subtyping. We sought to determine whether the distinction of the inflammatory breast cancer (IBC) phenotype from the non-IBC phenotype by transcriptomics could be sustained by methylomics. We performed methylation profiling on a cohort of IBC (N = 19) and non-IBC (N = 43) samples using the Illumina Infinium Methylation Assay. These results were correlated with gene expression profiles. Methylation values allowed separation of breast tumor samples into high and low methylation groups. This separation was significantly related to DNMT3B mRNA levels. The high methylation group was enriched for breast tumor samples from patients with distant metastasis and poor prognosis, as predicted by the 70-gene prognostic signature. Furthermore, this tumor group tended to be enriched for IBC samples (54% vs. 24%) and samples with a high genomic grade index (67% vs. 38%). A set of 16 CpG loci (14 genes) correctly classified 97% of samples into the low or high methylation group. Differentially methylated genes appeared to be mainly related to focal adhesion, cytokine-cytokine receptor interactions, Wnt signaling pathway, chemokine signaling pathways and metabolic processes. Comparison of IBC with non-IBC led to the identification of only four differentially methylated genes (TJP3, MOGAT2, NTSR2 and AGT). A significant correlation between methylation values and gene expression was shown for 4,981 of 6,605 (75%) genes. A subset of clinical samples of breast cancer was characterized by high methylation levels, which coincided with increased DNMT3B expression. Furthermore, an association was observed with molecular signatures indicative of poor patient prognosis. The results of the current study also suggest that aberrant DNA methylation is not the main force driving the molecular biology of IBC.
    Full-text · Article · Sep 2010 · PLoS ONE
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