• Asian Pacific Journal of Cancer Prevention
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• 제13권1호
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• pp.371-376
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• 2012

Background: Caveolin-1 (CAV-1), encoding the structural component of cellular caveolae, is a suggested tumor suppressor gene involved in cell signalling. Aberrant promoter methylation of CAV-1 is associated with inactivation of expression. We previously observed CAV-1 mutations in breast cancers and therefore devised this study to examine the hypermethylation status of the promoter region of CAV-1 with reference to breast cancer progression and development. Methods: Hypermethylation status of CAV-1 was analyzed by methylation specific PCR. Loss of expression of the CAV-1 gene was further evaluated by semi-quantitative rt-PCR. Results: 28/130 (21.5%) breast cancer cases showed promoter hypermethylation with reduced CAV-1 expression levels when compared with adjacent normal breast tissue. CAV-1 gene hypermethylation was significantly related to menopausal status, histopathological grade and age. Conclusion: The rationale of our study is that CAV-1 gene is transcriptionally repressed in breast cancer cells due to hypermethylation. Our results reveal that promoter hypermethylation and loss of expression of the CAV-1 gene is an important alternative mechanism for inactivation of CAV-1 leading to complete gene silencing.

• Asian Pacific Journal of Cancer Prevention
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• 제16권3호
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• pp.1235-1239
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• 2015

Background: Fragile histidine triad (FHIT) gene is a tumor suppressor gene which involved in breast cancer pathogenesis. Epigenetics alterations in FHIT contributes to tumorigenesis of breast cancer. Objective: Our objective was to study FHIT promoter region hypermethylation in Egyptian breast cancer patients and its association with clinicopathological features. Materials and Methods: Methylation-specific polymerase chain reaction was performed to study the hypermethylation of FHIT promoter region in 20 benign breast tissues and 30 breast cancer tissues. Results: The frequency of hypermethylation of FHIT promoter region was significantly increased in breast cancer patients compared to bengin breast disease patients. The Odd's ratio (95%CI) of development of breast cancer in individuals with FHIT promoter hypermethylation (MM) was 11.0 (1.22-250.8). There were also significant associations between FHIT promoter hypermethylation and estrogen, progesterone receptors negativity, tumor stage and nodal involvment in breast cancer pateints. Conclusions: Our results support an association between FHIT promotor hypermethylation and development of breast cancer in Egyptian breast cancer patients. FHIT promoter hypermethylation is associated with some poor prognostic features of breast cancer.

• Journal of Preventive Medicine and Public Health
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• 제45권4호
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• pp.251-258
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• 2012

Objectives: The purpose of this paper was to elucidate the potential methylation levels of adjacent normal and cancer tissues by comparing them with normal colorectal tissues, and to describe the correlations between the methylation and clinical parameters in Korean colorectal cancer (CRC) patients. Methods: Hypermethylation profiles of nine genes (RASSF1, APC, $p16^{INK4a}$, Twist1, E-cadherin, TIMP3, Smad4, COX2, and ABCB1) were examined with 100 sets of cancer tissues and 14 normal colorectal tissues. We determined the hypermethylation at a given level by a percent of methylation ratio value of 10 using quantitative methylation real-time polymerase chain reaction. Results: Nine genes' hypermethylation levels in Korean CRC patient tissues were increased more higher than normal colorectal tissues. However, the amounts of $p16^{INK4a}$ and E-cadherin gene hypermethylation in normal and CRC tissues were not significantly different nor did TIMP3 gene hypermethylation in adjacent normal and cancer tissues differ significantly. The hypermethylation of TIMP3, Ecadherin, ABCB1, and COX2 genes among other genes were abundantly found in normal colorectal tissues. The hypermethylation of nine genes' methylation in cancer tissues was not significantly associated with any clinical parameters. In Cohen's kappa test, it was moderately observed that RASSF1 was related with E-cadherin, and Smad4 with ABCB1 and COX2. Conclusions: This study provides evidence for different hypermethylation patterns of cancer-associated genes in normal and CRC tissues, which may serve as useful information on CRC cancer progression.

• Asian Pacific Journal of Cancer Prevention
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• 제16권13호
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• pp.5343-5348
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• 2015

Promoter hypermethylation of the runt-related transcription factor 3 (RUNX3) gene is associated with increased risk of hepatocellular carcinoma (HCC). Oxidative stress plays a vital role in both carcinogenesis and progression of HCC. However, whether oxidative stress and RUNX3 hypermethylation in HCC have a cause-and-effect relationship is not known. In this study, plasma protein carbonyl and total antioxidant capacity (TAC) in patients with hepatitis B virus (HBV)-associated HCC (n=60) and age-matched healthy subjects (n=80) was determined. RUNX3 methylation in peripheral blood mononuclear cells (PBMC) of subjects was measured by methylation-specific PCR. Effect of reactive oxygen species (ROS) on induction of RUNX3 hypermethylation in HCC cells was investigated. Plasma protein carbonyl content was significantly higher, whereas plasma TAC was significantly lower, in HCC patients than healthy controls. Based on logistic regression, increased plasma protein carbonyl and decreased plasma TAC were independently associated with increased risk for HCC. PBMC RUNX3 methylation in the patient group was significantly greater than in the healthy group. RUNX3 methylation in hydrogen peroxide ($H_2O_2$)-treated HepG2 cells was significantly higher than in untreated control cells. In conclusion, increase in oxidative stress in Thai patients with HBV-associated HCC was demonstrated. This oxidative increment was independently associated with an increased risk for HCC development. RUNX3 in PBMC was found to be hypermethylated in the HCC patients. In vitro, RUNX3 hypermethylation was experimentally induced by $H_2O_2$. Our findings suggest that oxidative stress is a cause of RUNX3 promoter hypermethylation in HCC cells.

• Asian Pacific Journal of Cancer Prevention
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• 제16권4호
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• pp.1599-1603
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• 2015

Background: Epigenetic silencing of tumor suppressor genes due to promoter hypermethylation is one of the frequent mechanisms observed in cancers. Hypermethylation of several tumor suppressor genes involved in cell cycle regulation has been reported in many types of tumors including oral squamous cell carcinomas. LATS1 (Large Tumor Suppressor, isoform 1) is a novel tumor suppressor gene that regulates cell cycle progression by forming complexes with the cyclin dependent kinase, CDK1. Promoter hypermethylation of the LATS1 gene has been observed in several carcinomas and also has been linked with prognosis. However, the methylation status of LATS1 in oral squamous cell carcinomas is not known. As oral cancer is one of the most prevalent forms of cancer in India, the present study was designed to investigate the methylation status of LATS1 promoter and associate it with histopathological findings in order to determine any associations of the genetic status with stage of differentiation. Materials and Methods: Tumor chromosomal DNA isolated from biopsy tissues of thirteen oral squamous cell carcinoma biopsy tissues were subjected to digestion with methylation sensitive HpaII enzyme followed by amplification with primers flanking CCGG motifs in promoter region of LATS1 gene. The PCR amplicons were subsequently subjected to agarose gel electrophoresis along with undigested amplification control. Results: HpaII enzyme based methylation sensitive PCR identified LATS1 promoter hypermethylation in seven out of thirteen oral squamous cell carcinoma samples. Conclusions: The identification of LATS1 promoter hypermethylation in seven oral squamous cell carcinoma samples (54%), which included one sample with epithelial dysplasia, two early invasive and one moderately differentiated lesions indicates that the hypermethylation of this gene may be one of the early event during carcinogenesis. To the best of our knowledge, this is the first study to have explored and identified positive association between LATS1 promoter hypermethylation with histopathological features in oral squamous cell carcinomas.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제34권2호
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• pp.135-140
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• 2008

Loss of E-cadherin (E-cad) expression has been found in multiple cancers and is postulated to facilitate tumor cell dissociation and metastais. Promotor methylation may provides an alternative pathway for loss of gene function. This study evaluated the role of hypermethylation in the down-regulation of E-cad in oral squamous cell carcinoma (OSCC). We examined the E-cad expression by immunohistochemical staining and detected methylation status by methylation-specific polymerase chain reaction (MSP) in 20 OSCC tissues. Overally, 12 (60%) cases of hypermethylation of E-cad were detected and we found there were no correlation between methylation and age, histologic grade, lympn node metastasis, tumor size and clinical stage. However, Eleven (73.3%) of 15 samples which was negative for E-cad staining showed hypermethylation of E-cad promotor region. On the other hand, only one (20%) of 5 E-cad positive sample was observed with methylated status. The underexpression of E-cad was found to be related to promotor hypermethylation (p=0.035). In conclusion, we suggest that hypermethylation play a role in inactivation of E-cad gene and may be a appreciable biomarker for diagnosis and treatment of OSCC.

• Asian Pacific Journal of Cancer Prevention
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• 제17권6호
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• pp.2757-2760
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• 2016

Gastric cancer (GC) is the fourth most prevalant cancer and the second leading cause of cancer-related mortality worldwide. As in other cancers gastric carcinogenesis is multifactorial involving environmental, genetic and epigenetic components. Epigenetic silencing due to hypermethylation of tumour suppressor genes is one of the key events in gastric carcinogenesis. This study was aimed to analyse the hypermethylation status of the E-Cadherin (CDH1) gene promoter in GCs in the ethnic Kashmiri population. In this study a total of 80 GC patients were recruited. Hypermethylation in tumour tissue was detected by methylation specific PCR (MS-PCR). Hypermethylation of CDH1 promoter was observed in 52 (65%) of gastric carcinoma cases which was significantly much higher than adjacent normal tissue [$p{\leq}0.0001$]. Further the frequency of CDH1 promoter methylation was significantly different with intestinal and diffuse types of gastric cancer [55.7% vs 82.1%; p<0.05]. Moreover females and cases with lymph node invasion had higher frequencies of CDH1 hypermethylation [$P{\leq}0.05$]. Thus the current data indicate a vital role of epigenetic alteration of CDH1 in the causation and development of gastric cancer, particularly of diffuse type, in our population.

• Asian Pacific Journal of Cancer Prevention
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• 제15권22호
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• pp.9607-9610
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• 2014

Breast cancer, a leading cause of death among women in most countries worldwide, is rapidly increasing in incidence in Vietnam. One of biomarkers is the disruption of the genetic material including epigenetic changes like DNA methylation. With the aim of finding hypermethylation at CpG islands of promoter of BRCA1 gene, belonged to the tumor suppressor gene family, as the biomarker for breast cancer in Vietnamese population, sensitive methyl specific PCR (MSP) was carried out on 115 samples including 95 breast cancer specimens and 20 normal breast tissues with other diseases which were obtained from Ho Chi Minh City Medical Hospital, Vietnam. The result indicated that the frequency of BRCA1 hypermethylation reached 82.1% in the cases (p<0.001). In addition, the DNA hypermethylation of this candidate gene increased the possibility to be breast cancer with high incidence via calculated odd ratios (p<0.05). In conclusion, hypermethylation of this candidate gene could be used as the promising biomarker application with Vietnamese breast cancer patients.

• Asian Pacific Journal of Cancer Prevention
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• 제15권24호
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• pp.10585-10589
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• 2015

Breast cancer susceptibility gene 1 (BRCA1), mapped on chromosome 17q21, is implicated in the mechanisms of cellular DNA repair. Inactivation of this gene is involved in the development of many human cancers, including breast cancer. This study aimed to investigate the prognostic value of BRCA1 promoter hypermethylation and expression in breast cancer cases. Sixty-one breast cancers were examined for BRCA1 hypermethylation by methylation-specific polymerase chain reaction (PCR), and 45 paired normal breast tissues were analyzed for altered BRCA1 mRNA levels by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Aberrant methylation status in BRCA1 was detected in 15 of 61 cases (24.6%), while reduced expression was found in 7 of 45 (15.6%). BRCA1 hypermethylation was statistically associated with tumor grade III (p=0.04), a high frequency of stage IIB (p=0.02), and triple-negative phenotype (OR= 3.64, 95%CI =1.1-12.3, p=0.03). Our findings indicated that BRCA1 promoter hypermethylation is a useful prognostic marker for breast cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8451-8454
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• 2014

Objectives: Epidemiological studies have shown that molecular mechanisms underlying the development of lung cancers differ between smokers and unsmokers. Aberrant promoter methylation in some tumor suppressor genes is frequent in lung tumors from smokers but rare in those from non-smokers. Recently, many studies have investigated the association between cigarette smoking and RASSF1A gene promoter hypermethylation in lung cancer patients, but a unanimous conclusion could not be reached. We therefore performed this meta-analysis to derive a more precise estimation of any association. Study Design: An electronic search of PubMed and Chinese Biomedicine databases was conducted to select studies. A total of 19 case-control studies were chosen, and odds ratios (ORs) with confidence intervals (CIs) were used to assess the strength of associations. Results: The case-control studies covered 2, 287 lung cancer patients: 63.4%(1449) of the patients were smokers, 36.6% (838) were unsmokers. The overall results suggested that smokers with lung cancer had a 1.297-fold (95% CI: 1.066~1.580, p=0.010, p=0.087) higher risk for RASSF1A gene hypermethylation than the non-smokers. In the stratified analysis, an increased risk of RASSF1A gene hypermethylation in smokers than in non-smokers was found in Asian (OR=1.481, 95%CI: 1.179~1.861, p=0.001, p=0.186). Conclusions: This meta-analysis supports the idea that RASSF1A gene hypermethylation is associated with cigarette smoking-induced lung cancer.