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CHFR Promoter Hypermethylation Is Associated with Gastric Cancer and Plays a Protective Role in Gastric Cancer Process.

ABSTRACT: Background: Chromosomally unstable tumors account for 50% of gastric cancer. CHFR plays a role in controlling chromosomal instability and its inactivation will eventually lead to tumorigenesis. In addition to genetic deletion, DNA methylation could silence the expression of many cancer-related genes including CHFR. Its methylation was found to be associated with the initiation and progression of gastric cancer. Methods: We performed a meta-analysis involving methylation analyses of CHFR promoter in gastric cancer. Nineteen studies with 1,249 tumor tissues and 745 normal tissues had been included in current study. Results: We found that CHFR methylation was significantly higher in gastric cancer (studies numbers = 15, cases/controls = 862/745, odds ratio (OR) = 7.46, 95% confidence index (95% CI) = 4.99-11.14). Methylation array data was also obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas network (TCGA). There were 7 out of 13 CHFR methylation probes target to the same CpG island region (hg19, 131973620-131975130) showed the CHFR methylation was higher in gastric cancers than normal controls. Eight probes showed CHFR promoter hypermethylation was associated with longer overall survival of gastric cancer patients (Hazard Ratio < 1). Conclusions: The CHFR promoter hypermethylation was associated with gastric cancer and played a protective role in gastric cancer process. Its methylation could be a potential biomarker for the diagnosis and prognosis of gastric cancer.

SUBMITTER: Dai D

PROVIDER: S-EPMC6400794 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CHFR Promoter Hypermethylation Is Associated with Gastric Cancer and Plays a Protective Role in Gastric Cancer Process.

Dai Dongjun D Zhou Bingluo B Xu Wenxia W Jin Hongchuan H Wang Xian X

Journal of Cancer 20190129 4

<b>Background</b>: Chromosomally unstable tumors account for 50% of gastric cancer. CHFR plays a role in controlling chromosomal instability and its inactivation will eventually lead to tumorigenesis. In addition to genetic deletion, DNA methylation could silence the expression of many cancer-related genes including CHFR. Its methylation was found to be associated with the initiation and progression of gastric cancer. <b>Methods</b>: We performed a meta-analysis involving methylation analyses of ...[more]

PMID: 30854101

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Project description:Gastric cancer (GC) is a common cause of cancer-related death. The etiology and pathogenesis of GC remain unclear, with genetic and epigenetic factors playing an important role. Previous studies investigated the association of GC with many genetic variants in and promoter hypermethylation of E-cadherin gene (CDH1), with conflicting results reported.To clarify this inconsistency, we conducted updated meta-analyses to assess the association of genetic variants in and the promoter hypermethylation of CDH1 with GC, including C-160A (rs16260) and other less-studied genetic variants,Data sources were PubMed, Cochrane Library, Google Scholar, Web of Knowledge, and HuGE, a navigator for human genome epidemiology.Study eligibility criteria and participant details are as follows: studies were conducted on human subjects; outcomes of interest include GC; report of genotype data of individual genetic variants in (or methylation status of) CDH1 in participants with and without GC (or providing odds ratios [OR] and their variances).Study appraisal and synthesis methods included the use of OR as a measure of the association, calculated from random effects models in meta-analyses. We used I for the assessment of between-study heterogeneity, and publication bias was assessed using funnel plot and Egger test.A total of 33 studies from 30 published articles met the eligibility criteria and were included in our analyses. We found no association between C-160A and GC (OR?=?0.88; 95% confidence interval [CI], 0.71-1.08; P?=?0.215), assuming an additive model (reference allele C). C-160A was associated with cardia (OR?=?0.21; 95% CI, 0.11-0.41; P?=?2.60?×?10), intestinal (OR?=?0.66; 95% CI, 0.49-0.90; P?=?0.008), and diffuse GC (OR?=?0.57; 95% CI, 0.40-0.82; P?=?0.002). The association of C-160A with noncardia GC is of bottom line significance (OR?=?0.65; 95% CI, 0.42-1.01; P?=?0.054). Multiple other less-studied genetic variants in CDH1 also exhibited association with GC. Gene-based analysis indicated a significant cumulative association of genetic variants in CDH1 with GC (all Ps <10). Sensitivity analysis excluding studies not meeting Hardy-Weinberg equilibrium (HWE) yielded similar results. Analysis by ethnic groups revealed significant association of C-160A with cardia GC in both Asian and whites, significant association with noncardia GC only in Asians, and no significant association with intestinal GC in both ethnic groups. There was significant association of C160-A with diffuse GC in Asians (P?=?0.011) but not in whites (P?=?0.081). However, after excluding studies that violate HWE, this observed association is no longer significant (P?=?0.126). We observed strong association of promoter hypermethylation of CDH1 with GC (OR?=?12.23; 95% CI, 8.80-17.00; P?=?1.42?×?10), suggesting that epigenetic regulation of CDH1 could play a critical role in the etiology of GC.Limitations of this study are as follows: we could not adjust for confounding factors; some meta-analyses were based on a small number of studies; sensitivity analysis was limited due to unavailability of data; we could not test publication bias for some meta-analyses due to small number of included studies.We found no significant association of the widely studied genetic variant C-160A, but identified some other genetic variants showing significant association with GC. Future studies with large sample sizes that control for confounding risk factors and/or intensively interrogate CpG sites in CDH1 are needed to validate the results found in this study and to explore additional epigenetic loci that affect GC risk.

Project description:Gastric cancer (GC) remains one of the most common digestive cancers worldwide; however, most patients present at an advanced stage at initial diagnosis. Zic1 is a novel candidate tumor suppressor gene that is epigenetically silenced in GC. In this study, we investigated Zic1 promoter methylation in plasma DNA as a novel molecular marker for the early diagnosis and monitoring of GC. Methylation-specific polymerase chain reaction (MSP) assay was performed to detect Zic1 promoter methylation in plasma DNA from 20 healthy subjects, 50 gastric intraepithelial neoplasia patients, and 104 GC patients. The Zic1 promoter methylation rate in the plasma samples from the healthy control group was 0%, but it reached 54.0% in the intraepithelial neoplasia group and 60.6% in the GC group. The latter two values were significantly higher than that found in the healthy control group (p < 0.05), with a 100% specificity for intraepithelial neoplasia and GC diagnosis. The positive predictive value of plasma Zic1 promoter methylation for the diagnosis of intraepithelial neoplasia and GC was 100%. Methylation status in the GC group was not significantly associated with tumor size, tumor differentiation, lymph node metastasis, TNM staging, or tumor invasion (p > 0.05). Assessment of the significance of detection of the carcino-embryonic antigen (CEA) level and Zic1 promoter methylation rate for GC diagnosis revealed that the sensitivity of Zic1 promoter methylation was significantly higher than that of the CEA level as a marker and that the combined measurement of these two indices (parallel testing) improved sensitivity. Taken together, our results suggest that the Zic1 promoter methylation rate in plasma-derived DNA is of great significance for the early screening of GC and monitoring of tumorigenesis. Zic1 promoter methylation may serve as a novel non-invasive plasma biomarker for the early detection of GC and for risk assessment in high-risk populations. The combined measurement of the Zic1 promoter methylation rate and CEA level (parallel testing) may enhance the current guidelines for the early diagnosis of GC.

Dataset Information

CHFR Promoter Hypermethylation Is Associated with Gastric Cancer and Plays a Protective Role in Gastric Cancer Process.

Publications

CHFR Promoter Hypermethylation Is Associated with Gastric Cancer and Plays a Protective Role in Gastric Cancer Process.

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