Exploring the Interplay Between Vitamin B₁₂-related Biomarkers, DNA Methylation, and Gene-Nutrition Interaction in Esophageal Precancerous Lesions

Background: Vitamin B₁₂ depletion has been suggested to be associated with esophageal precancerous lesions (EPL). However, the potential mechanisms remain unclear.

Aims: This study aims to evaluate the role of vitamin B₁₂ and its regulated epigenetic modification in EPL and provide preliminary information on the identification of potential molecular biomarkers for the early prediction of EPL.

Methods: We collected information and samples from the Early Diagnosis and Early Treatment Project of Esophageal Cancer database from 200 EPL cases and 200 matched controls. Vitamin B₁₂, one-carbon metabolism biomarkers, genetic polymorphism of TCN2 C776G, and DNA methylation were compared. Preliminarily identified candidate promoters of differentially methylated CpG positions were further verified by targeted bisulfite sequencing.

Results: EPL cases had significantly lower serum levels of vitamin B₁₂ and transcobalamin II, and higher serum levels of homocysteine and 5-methyltetrahydrofolate than controls. The TCN2 C776G polymorphism was found to be associated with susceptibility to EPL and may interact with vitamin B₁₂ nutritional status to influence the risk of EPL in male subjects. In addition, global hypomethylation related to vitamin B₁₂ depletion was observed in EPL cases, along with region-specific hypermethylation of UGT2B15 and FGFR2 promoters.

Conclusions: This study suggests that vitamin B₁₂ depletion may be associated with aberrant DNA methylation and increased risk of EPL through the one-carbon metabolism pathway, presents that the TCN2 C776G polymorphism may interact with vitamin B₁₂ nutritional status to affect EPL risk in males, and also identifies specific locations in the UGT2B15 and FGFR2 promoters with potential as promising molecular biomarkers.