Global DNA methylation and genetic factors associated with folate metabolism on carcinogenesis in pancreatic cancer.

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The study aimed to elucidate the relationship between global DNA hypomethylation characteristics of cancer and genetic polymorphisms of MTRR and MTHFR which are most evident in the folate metabolic pathway. To determine the functional activities in genetic polymorphisms associated with an amino acid change, we constructed cDNA with variation of MTHFR and MTRR. Total DNA methylation was determined by measuring the incorporation of methyl groups from 3H- SAM. We found that the exogenous MTHFR protein was produced at lower levels in the MTHFR transfectants harboring Val222 or Ala429 than in the wild-type. In contrast, exogenous MTRR protein showed no obvious differences between the Met22 variants and wild-type. MTHFR transfectants showed markedly decreased Hcy in culture media and a lower level of DNA methylation than did the control. The results indicate that polymorphic genes related to folate metabolism are involved in carcinogenesis through modulation of the methylation status.