The methylenetetrahydrofolate reductase C677T mutation induces cell‐specific changes in genomic DNA methylation and uracil misincorporation: A possible molecular basis for the site‐specific cancer risk modification

• Published in: International journal of cancer Vol. 124; no. 9; pp. 1999 - 2005
• Main Authors: Sohn, Kyoung‐Jin, Jang, Hyeran, Campan, Mihaela, Weisenberger, Daniel J., Dickhout, Jeffrey, Wang, Yi‐Cheng, Cho, Robert C., Yates, Zoe, Lucock, Mark, Chiang, En‐Pei, Austin, Richard C., Choi, Sang‐Woon, Laird, Peter W., Kim, Young‐In
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2009; Wiley-Blackwell
• Subjects: Biological and medical sciences; Blotting, Western; breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; CpG Islands; DNA Damage - genetics; DNA Methylation; folate; Folic Acid - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Genotype; Homocysteine - metabolism; Humans; Medical sciences; Methionine - metabolism; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; MTHFR C677T polymorphism; Mutation - genetics; Polymorphism, Genetic - genetics; Risk Factors; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumor Cells, Cultured; Tumors; Uracil - metabolism; uracil misincorporation; Methylenetetrahydrofolate reductase (NADPH); Modification; Breast disease; Genetic variability; Folate; Site specificity; Colon cancer; Cancerology; DNA methylation; Intestinal disease; Genetics; uracil misincorporation; Enzyme; Genotype; Breast cancer; Malignant tumor; Colonic disease; Mammary gland diseases; Risk factor; Digestive diseases; Chromosome DNA; Oxidoreductases; MTHFR C677T polymorphism; Molecular biology; Methylation; Uracil; Cancer; Polymorphism
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24003

The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased risk of colon cancer although it may increase the risk of breast cancer. This polymorphism is associated with changes in intracellular folate cofactors, which may affect DNA methylation and synthesis via altered one‐carbon transfer reactions. We investigated the effect of this mutation on DNA methylation and uracil misincorporation and its interaction with exogenous folate in further modulating these biomarkers of one‐carbon transfer reactions in an in vitro model of the MTHFR 677T mutation in HCT116 colon and MDA‐MB‐435 breast adenocarcinoma cells. In HCT116 cells, the MTHFR 677T mutation was associated with significantly increased genomic DNA methylation when folate supply was adequate or high; however, in the setting of folate insufficiency, this mutation was associated with significantly decreased genomic DNA methylation. In contrast, in MDA‐MB‐435 cells, the MTHFR 677T mutation was associated with significantly decreased genomic DNA methylation when folate supply was adequate or high and with no effect when folate supply was low. The MTHFR 677T mutation was associated with a nonsignificant trend toward decreased and increased uracil misincorporation in HCT116 and MDA‐MB‐435 cells, respectively. Our data demonstrate for the first time a functional consequence of changes in intracellular folate cofactors resulting from the MTHFR 677T mutation in cells derived from the target organs of interest, thus providing a plausible cellular mechanism that may partly explain the site‐specific modification of colon and breast cancer risks associated with the MTHFR C677T mutation. © 2008 Wiley‐Liss, Inc.