Friso Simonetta, Girelli Domenico, Trabetti Elisabetta, Olivieri Oliviero, Guarini Patrizia, Pignatti Pier Franco, Corrocher Roberto, Choi Sang-Woon
Department of Clinical and Experimental Medicine, University of Verona, Policlinico Giambattista Rossi, Piazza Ludovico Antonio Scuro, 10, 37134 Verona, Italy.
Cancer Epidemiol Biomarkers Prev. 2005 Apr;14(4):938-43. doi: 10.1158/1055-9965.EPI-04-0601.
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.
亚甲基四氢叶酸还原酶（MTHFR）在一碳代谢中平衡叶酸辅酶库，参与DNA合成与甲基化过程，二者均与癌症发生有关。流行病学研究表明，MTHFR基因中的两种功能性多态性，即677C>T和1298A>C，与癌症风险增加相关。我们旨在分析198名受试者的淋巴细胞DNA，以评估MTHFR 1298A>C多态性和叶酸状态对基因组DNA甲基化的影响，这可能是MTHFR多态性与癌症易感性之间关系的潜在机制。与1298AC或1298CC基因型相比，1298AA野生型基因型携带者的基因组DNA甲基化水平较低[分别为3.72 ng 5-甲基-2'-脱氧胞苷（5-mCyt）/μg DNA，而8.59或6.79 ng，P < 0.0001和P = 0.007]。根据血浆叶酸状态评估DNA甲基化时，只有叶酸水平低的1298AA个体显示DNA甲基化减少（P < 0.0001）。此外，当在低叶酸状态下同时评估两种MTHFR多态性时，与1298AA/677CC（3.11 ng 5-mCyt/μg DNA对7.29 ng，P = 0.001）和1298CC/677CC基因型（3.11 ng 5-mCyt/μg DNA对7.14 ng，P = 0.004）相比，只有1298AA/677TT的DNA甲基化降低。然而，1298AA组中677TT突变体的高发生率（79%）以及1298AA/677CC和1298CC/677CC组合基因型的相似生化特征表明，影响1298AA中DNA甲基化的基因-营养素相互作用主要是由于677TT基因型的共存，并且1298A>C多态性可能不是通过这种相互作用而是通过一碳代谢中的另一条途径发挥其保护作用。有必要进行进一步的机制研究，以探讨单多态性以及MTHFR组合基因型如何对癌症易感性产生影响。
