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The MTHFR 1298A>C polymorphism and genomic DNA methylation in human lymphocytes.
Cancer Epidemiol Biomarkers Prev. 2005 Apr; 14(4):938-43.CE

Abstract

Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one-carbon metabolism for DNA synthesis and methylation, both implicated in carcinogenesis. Epidemiologic studies have shown that two functional polymorphisms in MTHFR gene, 677C>T and 1298A>C, are related to increased cancer risk. We aimed to analyze lymphocyte DNA from 198 subjects to evaluate the MTHFR 1298A>C polymorphism and folate status affecting genomic DNA methylation as a possible mechanism underlying the relationship between MTHFR polymorphisms and cancer susceptibility. Carriers of the 1298AA wild-type genotype showed lower genomic DNA methylation compared with 1298AC or 1298CC genotypes [3.72 versus 8.59 or 6.79 ng 5-methyl-2'-deoxycytidine (5-mCyt)/microg DNA, P < 0.0001 and P = 0.007, respectively]. When DNA methylation was evaluated according to plasma folate status, only 1298AA with low folate levels revealed diminished DNA methylation (P < 0.0001). Moreover, when the two MTHFR polymorphisms were concomitantly evaluated at the low folate status, DNA methylation was reduced only in 1298AA/677TT compared with 1298AA/677CC (3.11 versus 7.29 ng 5-mCyt/microg DNA, P = 0.001) and 1298CC/677CC genotypes (3.11 versus 7.14 ng 5-mCyt/microg DNA, P = 0.004). However, the high prevalence of 677TT mutants within the 1298AA group (79%) and the similar biochemical features of 1298AA/677CC and 1298CC/677CC combined genotypes suggest that the gene-nutrient interaction affecting DNA methylation in 1298AA is mainly due to the coexistence of the 677TT genotype and that the 1298A>C polymorphism may convey its protective effect not through this interaction but through another pathway in one-carbon metabolism. Further mechanistic studies are warranted to investigate how single polymorphisms as well as MTHFR combined genotypes exert their effect on cancer susceptibility.

Authors+Show Affiliations

Department of Clinical and Experimental Medicine, University of Verona, Policlinico Giambattista Rossi, Piazza Ludovico Antonio Scuro, 10, 37134 Verona, Italy. simonetta.friso@univr.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15824167

Citation

Friso, Simonetta, et al. "The MTHFR 1298A>C Polymorphism and Genomic DNA Methylation in Human Lymphocytes." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, vol. 14, no. 4, 2005, pp. 938-43.
Friso S, Girelli D, Trabetti E, et al. The MTHFR 1298A>C polymorphism and genomic DNA methylation in human lymphocytes. Cancer Epidemiol Biomarkers Prev. 2005;14(4):938-43.
Friso, S., Girelli, D., Trabetti, E., Olivieri, O., Guarini, P., Pignatti, P. F., Corrocher, R., & Choi, S. W. (2005). The MTHFR 1298A>C polymorphism and genomic DNA methylation in human lymphocytes. Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, 14(4), 938-43.
Friso S, et al. The MTHFR 1298A>C Polymorphism and Genomic DNA Methylation in Human Lymphocytes. Cancer Epidemiol Biomarkers Prev. 2005;14(4):938-43. PubMed PMID: 15824167.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The MTHFR 1298A>C polymorphism and genomic DNA methylation in human lymphocytes. AU - Friso,Simonetta, AU - Girelli,Domenico, AU - Trabetti,Elisabetta, AU - Olivieri,Oliviero, AU - Guarini,Patrizia, AU - Pignatti,Pier Franco, AU - Corrocher,Roberto, AU - Choi,Sang-Woon, PY - 2005/4/13/pubmed PY - 2005/6/29/medline PY - 2005/4/13/entrez SP - 938 EP - 43 JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology JO - Cancer Epidemiol Biomarkers Prev VL - 14 IS - 4 N2 - Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one-carbon metabolism for DNA synthesis and methylation, both implicated in carcinogenesis. Epidemiologic studies have shown that two functional polymorphisms in MTHFR gene, 677C>T and 1298A>C, are related to increased cancer risk. We aimed to analyze lymphocyte DNA from 198 subjects to evaluate the MTHFR 1298A>C polymorphism and folate status affecting genomic DNA methylation as a possible mechanism underlying the relationship between MTHFR polymorphisms and cancer susceptibility. Carriers of the 1298AA wild-type genotype showed lower genomic DNA methylation compared with 1298AC or 1298CC genotypes [3.72 versus 8.59 or 6.79 ng 5-methyl-2'-deoxycytidine (5-mCyt)/microg DNA, P < 0.0001 and P = 0.007, respectively]. When DNA methylation was evaluated according to plasma folate status, only 1298AA with low folate levels revealed diminished DNA methylation (P < 0.0001). Moreover, when the two MTHFR polymorphisms were concomitantly evaluated at the low folate status, DNA methylation was reduced only in 1298AA/677TT compared with 1298AA/677CC (3.11 versus 7.29 ng 5-mCyt/microg DNA, P = 0.001) and 1298CC/677CC genotypes (3.11 versus 7.14 ng 5-mCyt/microg DNA, P = 0.004). However, the high prevalence of 677TT mutants within the 1298AA group (79%) and the similar biochemical features of 1298AA/677CC and 1298CC/677CC combined genotypes suggest that the gene-nutrient interaction affecting DNA methylation in 1298AA is mainly due to the coexistence of the 677TT genotype and that the 1298A>C polymorphism may convey its protective effect not through this interaction but through another pathway in one-carbon metabolism. Further mechanistic studies are warranted to investigate how single polymorphisms as well as MTHFR combined genotypes exert their effect on cancer susceptibility. SN - 1055-9965 UR - https://www.unboundmedicine.com/medline/citation/15824167/The_MTHFR_1298A>C_polymorphism_and_genomic_DNA_methylation_in_human_lymphocytes_ L2 - http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=15824167 DB - PRIME DP - Unbound Medicine ER -