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 |
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| Authors: | Kyoung‐Jin Sohn Hyeran Jang Mihaela Campan Daniel J Weisenberger Jeffrey Dickhout Yi‐Cheng Wang Robert C Cho Zoe Yates Mark Lucock En‐Pei Chiang Richard C Austin Sang‐Woon Choi Peter W Laird Young‐In Kim |
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| Institution: | 1. Department of Medicine, University of Toronto, St. Michael's Hospital, Toronto, Ontario, Canada, M5S 1A8;2. Vitamin and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA;3. Department of Surgery and Biochemistry & Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA;4. McMaster University and the Henderson Research Center, McMaster University, Hamilton, Ontario, Canada, L8V 1C3;5. Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan;6. Department of Nutritional Sciences, University of Toronto, St. Michael's Hospital, Toronto, Ontario, Canada, M5S 1A8;7. Molecular Nutrition Laboratory, School of Environmental and Life Sciences, Ourimbah Campus, University of Newcastle, Australia, New South Wales 2258;8. Division of Gastroenterology, St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1W8;9. Fax: 416‐978‐8765. |
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| Abstract: | 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. |
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| Keywords: | MTHFR C677T polymorphism folate colon cancer breast cancer DNA methylation uracil misincorporation |
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