Methylation of the TFPI2 Gene Is Frequently Detected in Advanced Gastric Carcinoma

Department of Surgery, Showa University Fujigaoka Hospital, Aoba-ku, Yokohama, Japan.
Anticancer research (Impact Factor: 1.83). 10/2010; 30(10):4131-3.
Source: PubMed


Recently, Glockner et al. identified the methylation of TFPI2 as a frequent event in human colorectal cancer using a gene expression array-based strategy.
Methylation status of the TFPI2 gene was examined in primary carcinomas and the corresponding normal tissues derived from 38 patients with gastric cancer using quantitative methylation-specific PCR (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated.
Aberrant methylation of the TFPI2 gene was detected in 7 out of 38 (18%) primary gastric carcinomas, suggesting that the methylation of TFPI2 is frequently observed in gastric carcinomas. The clinicopathological data were correlated with the methylation results. A significant difference was observed in maximal tumour size (p=0.0084), extent of tumour (p=0.0068), and TNM stage (p=0.0392).
TFPI2 is frequently methylated in advanced gastric carcinomas.

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    ABSTRACT: Background and objective: The epigenetic silencing of tumor suppressor genes plays an important role in gliomagenesis. Recently, tissue factor pathway inhibitor 2 (TFPI-2) has been suggested as a tumor suppressor gene involved in tumorigenesis and metastasis in some cancers. However, to date, little is known about the methylation status of TFPI-2 gene in glioblastoma tissues. In this study, we aimed to investigate the methylation status of TFPI-2 promoter and its associations with patient prognosis in glioblastoma. Material and methods: The methylation status of TFPI-2 was investigated by methylation-specific polymerase chain reaction in 99 glioblastoma patients. The associations between patients' clinical variables and overall survival time were assessed. RESULTS. TFPI-2 was aberrantly methylated in 22.2% (22/99) of glioblastoma tumors, but was not methylated in normal brain samples. The survival of patients with glioblastoma differed significantly between the methylated and unmethylated TFPI-2 groups (P=0.047). The 2-year survival among patients carrying methylated TFPI-2 tumors was significantly lower compared with that of patients with unmethylated TFPI-2 (27% versus 4.7%, P=0.037). Conclusions: The present work demonstrated that the epigenetic inactivation of TFPI-2 by promoter hypermethylation was a frequent and tumor-specific event in glioblastoma, and TFPI-2 promoter methylation might be considered as a prognostic marker in glioblastoma.
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    ABSTRACT: Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes has led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.
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    ABSTRACT: Epigenetic modifications are important early events during carcinogenesis. In particular, hypermethylation of CpG islands in the promoter region of tumor suppressor genes is a well-known mechanism of gene silencing that contributes to cancer development and progression. Tissue factor pathway inhibitor 2 (TFPI-2) is a tumor suppressor involved in invasiveness inhibition. Although TFPI-2 transcriptional silencing, through promoter hypermethylation, has been widely reported in several human malignancies, it has never been explored in lymphoma. In the present study TFPI-2 methylation and gene expression have been investigated in canine Diffuse Large B-cell lymphomas (cDLBCL). The methylation level of 23 CpGs located within the TFPI-2 promoter was investigated by bisulfite-specific PCR and next generation amplicon deep sequencing (GS Junior 454, Roche) in 22 cDLBCLs and 9 controls. For the same specimens, TFPI-2 gene expression was assessed by means of Real-time RT-PCR. Sequence analysis clearly demonstrated that TFPI2 is frequently hypermethylated in cDLBCL. Hypermethylation of the TFPI-2 promoter was found in 77% of DLBCLs (17 out of 22) and in one normal lymph node. Globally, dogs with DLBCL showed a mean methylation level significantly increased compared to controls (p<0.01) and analysis of hypermethylation by site identified 19 loci out of 23 (82%) with mean methylation levels from 2- to 120-fold higher in cDLBCL. Gene expression analysis confirmed a significant down-regulation of TFPI-2 (p<0.05) in DLBCLs compared with normal lymph nodes, suggesting that TFPI-2 hypermethylation negatively regulates its transcription. In addition, a significant positive correlation (p<0.01) was found between TFPI-2 methylation levels and age providing the first indication of age-associated epigenetic modifications in canine DLBCL. To conclude, our findings demonstrated that epigenetic dysregulation of TFPI-2, leading to its reduced expression, is frequently detected in canine DLBCL. In the next future, the aberrant TFPI-2 promoter hypermethylation may be considered in association with prognosis and therapy.
    Full-text · Article · Apr 2014 · PLoS ONE

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