DNA methylation is a pivotal epigenetic modification that can be altered in precancerous lesions. As MTHFR is the key gene and metabolite in the one-carbon metabolism pathway that allows for the metabolism of homocysteine and the provision of methyl groups[23, 24], the MTHFR C677T polymorphism may be considered as a reliable factor for predicting the prognosis of gastric precancerous lesions[25, 26]. The reduced activity of the MTHFR enzyme resulting from TT mutation has been associated with alterations in methylation patterns and potentially aberrant DNA synthesis, repair, and chromosomal damage. This study evaluated the degree of atrophy and IM in different biopsies to examine whether the TT genotype confers an increased risk for developing moderate-to-severe lesions (moderate-to-severe atrophy or IM in any one biopsy). In addition, patients with the TT genotype were found to be at a higher risk of OLGA and OLGIM stages III-Ⅳ compared to patients with the CC + CT genotypes. It has been shown previously that OLGA stages I-II are associated with a lower risk while stages III-IV are associated with a higher risk of gastric cancer[28, 29]. Thus, in our study, the TT genotype was a risk factor for gastric precancerous lesions. It is noteworthy to mention that conflicting results have been reported on the influence of the MTHFR C677T polymorphism on precancerous lesions or cancer. Some studies have shown an increased risk of gastric cancer development among Asians and Caucasians[14, 30], while others studies have reported a negative association or null results[31, 32]. Conflicting results indicate that population-specific and geographical factors may account for this phenomenon.
In addition, we recommend the incisura biopsies should be routinely included in the biopsy sampling protocol for patients with the TT genotype for further screening of gastric cancer risk. The incisura is the main region for the early-onset of atrophic-metaplastic transformation. It may undergo more severe atrophic, metaplastic, and chronic inflammatory changes than the antrum and corpus [34, 35].
A cross-sectional serological study performed in Sweden showed an age-related trend with an increasing prevalence of AG in adults aged 35–44 years compared to those older than 44 years. The morbidity age for AG patients seems to be younger than previously thought. Previous studies suggested that the increasing prevalence of overweight and obese patients might contribute to this unexpected trend[36, 37]. In our AG population, we did not find such an association between the severity of AG and overweight or obesity (BMI shown in Table 1, P > 0.05). These observations in our study may be due to the fact that we did not establish a control group in the general population for comparison with AG patients, as was done in the study by Song et al. However, when we divided patients into two age groups (27–44 years and 45–80 years), the frequency of the TT genotype was much higher in the younger age group than in the older age group, indicating that AG patients with the TT genotype might have a younger morbidity age and a longer duration of illness. As a result, AG patients with the TT genotype may suffer from more severe gastric diseases. Previous studies have confirmed that aging is an independent risk factor for AG progression to gastric cancer. In general population, the prevalence of AG in persons over 40 years is double that in those under 40 years. In our study, however, the frequency of the TT genotype was lower in patients over 44 years of age. This may be due to some important transition of the dominant mechanism. Further research on the difference in MTHFR C677T genotype frequency in these two AG age groups is warranted.
Folate deficiencies may increase cancer risk by inducing uracil misincorporation during DNA synthesis, leading to chromosomal damage, DNA strand breaks, and impaired DNA repair, as well as DNA hypomethylation. The data from our study suggest that AG patients with the TT genotype have a higher rate of folate deficiency compared with those with the CC + CT genotypes (P = 0.001), which will theoretically bring a higher rate of hyperhomocysteinemia. However, in our study, this was not the case. No significant difference was observed (P = 0.819), indicating that the AG may be more of a direct cause of hyperhomocysteinemia, which is in good agreement with previous research. This phenomenon suggests that the AG factor may play a more important role in the presence of hyperhomocysteinemia than the MTHFR C677Tgenotype. As a result, AG patients are suggested to receive folic acid supplementation to reduce the risk of gastric cancer.
Although not statistically significant, patients with the TT genotype in our study showed a trend towards a higher frequency of more severe lesions according to the Kimura-Takemoto endoscopic classification. In addition, some studies have reported that the severity of endoscopic gastric atrophy according to the Kimura-Takemoto endoscopic classification is correlated with OLGA and OLGIM stages[21, 40]. In our study, however, the correlation was weak with a kappa value of 0.29.
To our knowledge, our study provides the first observation of an association between the MTHFR C677T polymorphism and gastric precancerous lesions. The results of this study suggest that the TT genotype is associated with more severe lesions. Based on our findings we propose that biopsy of the incisura in AG patients with the TT genotype will be useful for further screening of gastric cancer risk, especially for patients younger than 44 years. AG itself may be a contributing factor towards hyperhomocysteinemia. In addition, patients should be cautious about the potential risk of cardiovascular diseases in view of the association between hyperhomocysteinemia and vascular injury.
In conclusion, the effects of the MTHFR C677T polymorphism on gastric precancerous lesions have been systematically examined in this study. Based on our findings, we propose that MTHFR C677T genotyping could be useful in identifying patients at increased risk for moderate-to-severe atrophy or IM. Such screening may be valuable clinically in assessing the risk and prognosis of gastric precancerous lesions. In addition, AG patients should receive appropriate folic acid supplementation to prevent hyperhomocysteinemia. Further standardized research including well-designed and strictly implemented trials are required to confirm that the MTHFR C677T genetic polymorphism is an independent predictor of the severity of AG.