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Association of genetic polymorphisms in DNMT3A with the progression of gastric mucosal atrophy and susceptibility to gastric cancer in Japan.

ABSTRACT: The aim of the present study was to investigate whether single nucleotide polymorphisms in the DNMT3A gene are associated with susceptibility to gastric cancer in the Japanese population. The present case-control study examined the associations between single nucleotide polymorphisms (rs6733868 and rs13428812) in DNMT3A and cancer susceptibility in 343 patients with gastric cancer and 708 subjects without gastric malignancies on upper gastro-duodenal endoscopy. Of 708 controls, 409 were classified into two groups histologically: 99 cases with and 310 cases without gastric mucosal atrophy. Overall, homozygosity for the DNMT3A rs6733868 minor allele was significantly associated with a reduced risk of gastric cancer (odds ratio [OR], 0.621; 95% confidence interval [CI], 0.402-0.958; P=0.031), especially of the intestinal type (OR, 0.494; 95% CI, 0.274-0.890; P=0.019). In subjects >60 years, rs6733868 minor allele homozygosity was significantly associated with gastric cancer susceptibility. Carriers of the rs6733868 minor allele had a reduced risk of severe gastric mucosal atrophy (OR, 0.495; 95% CI, 0.299-0.826; P=0.0069). In addition, the number of minor alleles of both rs6733868 and rs13428812 was significantly correlated with the risk of Helicobacter pylori (HP) infection (P=0.0070 and P=0.0050, respectively). However, rs13428812 was not associated with severe gastric mucosal atrophy or gastric carcinogenesis. The present results suggest that DNMT3A polymorphisms serve roles in the progression from HP infection to gastric mucosal atrophy and gastric carcinogenesis in terms of degree and manner.

SUBMITTER: Jing W

PROVIDER: S-EPMC6396126 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Association of genetic polymorphisms in DNMT3A with the progression of gastric mucosal atrophy and susceptibility to gastric cancer in Japan.

Jing Wu W Otsuka Toshimi T Nakamura Masakatsu M Sakurai Naoko N Takano Hikaru H Hayashi Tasuku T Ota Masafumi M Nomura Tomoe T Hayashi Ranji R Shimasaki Takeo T Tahara Tomomitsu T Shibata Tomoyuki T Arisawa Tomiyasu T

Oncology letters 20190118 3

The aim of the present study was to investigate whether single nucleotide polymorphisms in the DNMT3A gene are associated with susceptibility to gastric cancer in the Japanese population. The present case-control study examined the associations between single nucleotide polymorphisms (rs6733868 and rs13428812) in DNMT3A and cancer susceptibility in 343 patients with gastric cancer and 708 subjects without gastric malignancies on upper gastro-duodenal endoscopy. Of 708 controls, 409 ...[more]

PMID: 30867787

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Project description:ObjectiveTo investigate the relationship between polymorphism of TNFRSF11 gene rs9533156 and rs2277438 and susceptibility to gastric cancer.MethodsA case-control study was conducted to select 577 cases of primary gastric cancer and 678 cases of normal control. We extracted whole blood genomic DNA and amplified the target gene fragment by PCR. The genotyping and allele were tested through the snapshot method.ResultsIn this case-control study, we observed that there was a difference in the genotype distribution of TNFRSF11 gene rs9533156 between the case group and the control group. The frequency distribution of TC heterozygous mutation in the case group was higher than that in the control group. The smoking rate in the case group (34.49%) was higher than that in the control group (27.29%), and the difference in frequency distribution between the two groups was statistically significant (P=0.006). Our findings suggest that TNFRSF11 rs9533156 is associated with susceptibility to GC, which is more evident among elderly patients (>62 years), nonsmokers, and patients who do not consume alcohol. The analysis of the relationship between the TNFSF11 gene rs9533156 site variant and clinical factors of gastric cancer showed that, compared with the tumor size <2 cm group, patients with tumor size ≥2 cm and whom carrying rs9533156 site mutations had a higher frequency distribution, and the difference was statistically significant (P=0.022). Compared with the nonhyperglycemic group, the frequency distribution of patients with rs9533156 site mutations in the diabetes group was higher, and the difference was statistically significant (P < 0.001).ConclusionThis study shows that there is a correlation between smoking and the occurrence of gastric cancer. Based on our research, the functional SNP TNFRSF11 TC genotype may be an indicator of individual susceptibility to GC. The mutation at rs9533156 may be related to the size of gastric cancer. The mutation rate of rs9533156 of TNFSF11 gene is higher in diabetic gastric cancer patients.

Project description:BackgroundCpG methylation of tumor suppressor genes occurs in the early stage of carcinogenesis. Detecting risk factors for aberrant CpG methylation is clinically important for predicting cancer development. DNA methyltransferase (DNMT) 3a is considered to play critical roles in the DNA methylation process during pathogenesis. In this study, we evaluated the association between DNMT3A polymorphisms (rs6733868 and rs13428812) and CpG methylation status in non-cancerous gastric mucosa.MethodsWe determined the DNMT3A genotype and CpG methylation status of 4 genes (p14ARF, p16INK4a, DAPK, and CDH1) in 510 subjects without gastric cancer. Helicobacter pylori (HP) infection status was determined by the rapid urease test, urea breath test, speculum examination, or serum antibody test. We determined the DNMT3A genotype using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). CpG methylation status was determined by methylation-specific polymerase chain reaction (MSP). When the methylated band was stronger than 10 ng/μL according to the DNA marker, we judged CpG island hypermethylation (CIHM) to be present. Associations between genotypes and susceptibilities were assessed by logistic regression analysis.ResultsThe minor allele frequencies of both polymorphisms (rs6733868 and rs13428812) were lower in the CpG methylated groups of each of the 4 genes (p14ARF, p16INK4a, DAPK, and CDH1). Using a dominant genetic model, rs6733868 was significantly associated with the hypermethylation of each gene, whereas rs13428812 was associated with the methylation of 3 genes (all except p14ARF). When low-CIHM was defined as 1 or 2 CpG islands methylated and high-CIHM was defined as 3 or more CpG islands methylated, carrying the minor allele of rs6733868 was associated with both decreased low- and high-CIHM, and that of rs13428812 also was associated with a decrease. Comparing low-CIHM with high-CIHM, carrying the minor alleles of rs6733868 or rs13428812 was related to decreased susceptibility to high-CIHM. In HP-infected subjects, carrying the minor alleles of rs6733868 or rs13428812 had a significantly greater association with decreased susceptibility to high-CIHM.ConclusionsOur study indicates that polymorphisms of DNMT3A are associated with the accumulation of gene methylation in gastric mucosa. Carrying the minor alleles of rs6733868 or rs13428812 inhibits aberrant gene methylations, which are typically enhanced by HP infection.

Dataset Information

Association of genetic polymorphisms in DNMT3A with the progression of gastric mucosal atrophy and susceptibility to gastric cancer in Japan.

Publications

Association of genetic polymorphisms in <i>DNMT3A</i> with the progression of gastric mucosal atrophy and susceptibility to gastric cancer in Japan.

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