MTHFR C677T polymorphism and differential methylation status in gastric cancer: an association with Helicobacter pylori infection

Abstract

MTHFR C677T and Helicobacter pylori infection are believed to play critical roles in the DNA methylation process, an epigenetic feature frequently found in gastric cancer. The aim of this study was to verify the associations between the MTHFR C677T polymorphism and the methylation status of three gastric cancer-related genes. The influence of H. pylori strains was also assessed. DNA extracted from 71 gastric tumor samples was available for MTHFR C677T genotyping by PCR-RFLP, promoter methylation identification by MS-PCR and H. pylori detection and posterior subtyping (cagA and vacA genes) by PCR. In the distal tumors, a positive correlation was found between the methylation of CDKN2A and the allele T carriers (r=0.357; p=0.009). Considering the eldest patients (age ≥60 years old), this correlation was even higher (r=0,417; p=0.014). H. pylori infection by highly pathogenic strains (cagA+/vacAs1m1) was also found correlated to promoter methylation of CDKN2A and the allele T carriers in distal tumors (r=0.484; p=0.026). No significant correlation was verified between MTHFR C677T genotype and promoter methylation status when we analyzed the general sample. DNA methylation in CDKN2A associated to the MTHFR 677T carrier is suggested to be a distal tumor characteristic, especially in those 60 years old or older, and it seems to depend on the infection by H. pylori cagA/vacAs1m1 strains.

<b><i>TP53</i></b> Codon 72 and Intron 3 Polymorphisms and Mutational Status in Gastric Cancer: An Association with Tumor Onset and Prognosis

“…Gastric adenocarcinoma is one of the most frequent malignancies worldwide and is globally the second leading cause of cancer-related deaths [1]. In this context, Brazil is one of the countries with a high incidence, mainly in the Southeast and Northeast regions [2].…”

The combination of methylenehydrofolate reductase C677T polymorphism screening and gastrointestinal tumor markers detection may be an early screening method for gastrointestinal cancer related to helicobacter pylori infection

“…This might because of the T SNP mutation, leading to the decrease of MTHFR enzyme activity and affecting the methylation of human gastric mucosa cells, which results in the integrity of gastric mucosa and fosters the colonization of H.pylori . 32 And H.pylori infection will further affect folic acid absorption and metabolism, 33 , 34 leading to the damage of gastric mucosa and inducing local chronic inflammation. 13 , 35 This was consistent with the results of our previous study that WBC in H.pylori infected subjects was higher than that in uninfected subjects 23 ( Table 1 ).…”

“…Recent studies have shown that MTHFR C677T polymorphism may lead to abnormal DNA and/or RNA synthesis, and can repair abnormalities and chromosome damage in gastric mucosa infected by H.pylori , 36 resulting in dysfunction of MTHFR enzyme and then affecting methylation 29 , 32 and making conditions for other carcinogenic factors to cause abnormal methylation of protooncogenes, 17 thus leading to the occurrence and development of gastrointestinal cancer. 37 In our study, H.pylori infection was associated with increased CEA and CA724 levels but not associated with CA199 levels ( Table 3 ), which was similar to the study of Xu MY, Cao B, et al.…”

Multifactorial Etiology of Gastric Cancer

“…H. pylori virulence seem to be also associated with differential methylation on enzymes involved in the pathway that generates S -adenosylmethionine, the universal donor of methyl groups in humans (183). In a study from Brazil, it was found that infection with virulent strains of H. pylori is associated with a polymorphism in the methylenetetrahydrofolate reductase gene ( MTHFR ) enzyme ( MTHFR C677T ) in patients 60 years old or older (184). In addition, hypermethylation of cell cycle controlling genes (E-cadherin and CDKN2A ) have been reported in patients infected with H. pylori (184–188).…”

“…In a study from Brazil, it was found that infection with virulent strains of H. pylori is associated with a polymorphism in the methylenetetrahydrofolate reductase gene ( MTHFR ) enzyme ( MTHFR C677T ) in patients 60 years old or older (184). In addition, hypermethylation of cell cycle controlling genes (E-cadherin and CDKN2A ) have been reported in patients infected with H. pylori (184–188). Regarding to E-cadherin (encoded by the gene CDH1 ), the hypermethylation of this gene seems to be directly related to the infection with H. pylori since its eradication by antibiotic treatment lead to a significant reduction of the methylation level (188).…”