2013 Fiscal Year Final Research Report

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

Research Project

Project/Area Number	23617037
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Integrated Nutrition Science
Research Institution	National Center of Neurology and Psychiatry
Principal Investigator	OHNAMI SHUMPEI 独立行政法人国立がん研究センター, 研究所, 支援施設長 (60291142)
Project Period (FY)	2011 – 2013
Keywords	MTRR / homocysteine / DNA methylation / MTHFR
Research Abstract	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.