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Prognostic Role of RASSF1A, SOX17 and Wif-1 Promoter Methylation Status in Cell-Free DNA of Advanced Gastric Cancer Patients.

ABSTRACT: Epigenetic modification of several genes is a key component in the development of gastric cancer. The methylation status of RASSF1A, SOX17 and Wif-1 genes was evaluated in the cell free circulating DNA of 70 patients with advanced gastric cancer, using methylation-specific PCR. Patients with higher cell-free DNA concentration seem to have lower PFS, than patients with lower cell-free DNA concentration (p = 0.001). RASSF1A was the tumor suppressor gene, most frequently methylated in metastatic gastric cancer patients, followed by SOX17 and Wif-1 (74.3%, 60.0% and 47.1%, respectively). Patients having the SOX17 promoter methylated, had lower progression free survival and overall survival, than unmethylated ones (p < 0.001). Patients having the Wif-1 promoter methylated, had lower progression free survival and overall survival, than unmethylated ones (p = 0.001). Patients having the RASSF1A promoter methylated, had lower progression free survival and overall survival, than unmethylated ones (p = 0.004). Promoter methylation of the examined genes was significantly associated with a decrease in progression free survival and overall survival, comparing to that of patients without methylation. Simultaneous methylation of the above genes was associated with even worse progression free survival and overall survival. The methylation of RASSF1A, SOX-17 and Wif-1 and genes, is a frequent epigenetic event in patients with advanced gastric cancer.

SUBMITTER: Karamitrousis EI

PROVIDER: S-EPMC8113658 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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Prognostic Role of RASSF1A, SOX17 and Wif-1 Promoter Methylation Status in Cell-Free DNA of Advanced Gastric Cancer Patients.

Karamitrousis Evangelos I EI Balgkouranidou Ioanna I Xenidis Nikolaos N Amarantidis Kyriakos K Biziota Eirini E Koukaki Triantafyllia T Trypsianis Grigorios G Karayiannakis Anastasios A Bolanaki Helen H Kolios George G Lianidou Evi E Kakolyris Stylianos S

Technology in cancer research & treatment 20210101

Epigenetic modification of several genes is a key component in the development of gastric cancer. The methylation status of RASSF1A, SOX17 and Wif-1 genes was evaluated in the cell free circulating DNA of 70 patients with advanced gastric cancer, using methylation-specific PCR. Patients with higher cell-free DNA concentration seem to have lower PFS, than patients with lower cell-free DNA concentration (p = 0.001). RASSF1A was the tumor suppressor gene, most frequently ...[more]

PMID: 33928818

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Project description:Claudin‑3 expression is associated with gastric cancer progression, but the role of epigenetic modifications remains unclear. We investigated methylation of the claudin‑3 promoter and expression profiles in gastric adenocarcinoma and their associations with clinicopathological characteristics and prognosis of the patients. A total of 122 patients with advanced gastric cancer [stage IIB‑IV, with lymph node (LN) metastasis] were enrolled. Each patient provided 4 tissue samples: normal gastric epithelium, intestinal metaplasia, primary tumor and metastatic LN. Claudin‑3 protein expression was examined by immunohistochemistry. Claudin‑3 promoter methylation was determined by methylation‑specific PCR and verified by bisulfite sequencing PCR. Claudin‑3 mRNA expression was measured by real‑time PCR in a subset of cases, and its correlation with protein expression was analyzed using Spearman correlation. Kaplan‑Meier survival analysis was performed (log‑rank test). Factors associated with survival were identified by Cox regression. The strong expression rate of claudin‑3 in intestinal metaplasia, primary tumor, metastatic LN and normal gastric epithelium was 91.8, 58.2, 30.3 and 13.9%, respectively. The promoter hypermethylation rate in intestinal metaplasia, primary tumor, normal gastric epithelium and metastatic LN was 5.7, 27.9, 36.9 and 49.2%, respectively. Claudin‑3 mRNA and protein expression were positively correlated (P<0.001) with normal gastric epithelium (rs=0.745), intestinal metaplasia (rs=0.876), primary gastric adenocarcinoma (rs=0.915) and metastatic LN (rs=0.819). Claudin‑3 mRNA expression was negatively correlated with claudin‑3 promoter methylation. Median patient survival was 38, 22 and 11 months in the hypomethylated, partially methylated and hypermethylated groups, respectively (P<0.001). Claudin‑3 promoter methylation status (HR: 5.67; 95% CI: 2.27‑14.17) but not claudin‑3 expression was an independent predictor of survival. Claudin‑3 promoter hypermethylation reduces claudin‑3 expression and independently predicts poor prognosis.

Project description:Background. Assessment of DNA methylation of specific genes is one approach to the diagnosis of cancer worldwide. Early stage detection is necessary to reduce the mortality rate of cancers, including those occurring in the stomach. For this purpose, tumor cells in circulating blood offer promising candidates for non-invasive diagnosis. Transcriptional inactivation of tumor suppressor genes, like PCDH10 and RASSF1A, by methylation is associated with progression of gastric cancer, and such methylation can therefore be utilized as a biomarker. Methods. The present research was conducted to evaluate DNA methylation in these two genes using blood samples of gastric cancer cases. Clinicopathological data were also analyzed and cumulative survival rates generated for comparison. Results. High frequencies of PCDH10 and RASSF1A methylations in the gastric cancer group were noted (94.1% and 83.2%, respectively, as compared to 2.97% and 5.45% in 202 matched controls). Most patients (53.4%) were in severe stage of the disease, with a median survival time of 8.4 months after diagnosis. Likewise, the patients with metastases, or RASSF1A and PCDH10 methylations, had median survival times of 7.3, 7.8, and 8.4 months, respectively. A Kaplan-Meier analysis showed that cumulative survival was significantly lower in those cases positive for methylation of RASSF1A than in their negative counterparts. Similarly, whereas almost 100% of patients positive for PCDH10 methylation had died after five years, none of the negative cases died over this period. Notably, the methylations of RASSF1A and PCDH10 were found to be higher in the late-stage patients and were also significantly correlated with metastasis and histology. Conclusions. PCDH10 and RASSF1A methylations in blood samples can serve as potential non-invasive diagnostic indicators in blood for gastric cancer. In addition to RASSF1A methylation, tumor stage proved to be a major prognostic factor in terms of survival rates.

Dataset Information

Prognostic Role of RASSF1A, SOX17 and Wif-1 Promoter Methylation Status in Cell-Free DNA of Advanced Gastric Cancer Patients.

Publications

Prognostic Role of RASSF1A, SOX17 and Wif-1 Promoter Methylation Status in Cell-Free DNA of Advanced Gastric Cancer Patients.

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