Methylenetetrahydrofolate reductase (MTHFR) and susceptibility for (pre)neoplastic cervical disease

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme regulating the metabolism of folate and methionine. The potential influence of MTHFR activity on DNA methylation and on the availability of uridylates and thymidylates for DNA synthesis and repair presents MTHFR as a candidate for being a cancer-predisposing gene. In the present study, we have examined a large study population to determine whether the C677T polymorphism at the MTHFR locus affects susceptibility for cervical cancer or its precursor, cervical intraepithelial neoplasia (CIN). In addition, we have investigated whether this polymorphism is causal, and not merely associated, by typing microsatellite markers in the region surrounding the MTHFR gene. A total of 311 CIN and 695 cervical cancer patients and 115 family-based and 586 unrelated controls was analysed. Association analysis showed a decreased cervical cancer risk for individuals heterozygous or homozygous for the T-allele, both for squamous cell carcinoma (heterozygous odds ration [OR] 0.66 [0.51-0.86]; homozygous OR 0.76 [0.49-1.16]) and adenocarcinoma (heterozygous OR 0.71 [0.49-1.03]; homozygous OR 0.34 [0.14-0.81]). No difference was found for high grade CIN (heterozygous OR 1.03 [0.76-1.40]; homozygous OR 0.91 [0.54-1.55]). A microsatellite haplotype containing the C allele was associated with an increased risk for cervical cancer and CIN (both among squamous cell carcinomas, adenocarcinomas and CIN II-III; OR = 2.61 [1.59-4.27]). Our study thus lends further support to the hypothesis that the MTHFR C677T polymorphism is involved in susceptibility cervical cancer but also illustrates that, despite the large sample size analysed, still larger studies are needed to establish fully the nature of this association.

The effects of polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) on the risk of cervical intraepithelial neoplasia and cervical cancer in Korean women

“…The genotyping rates in the present study were also very high for each locus, and the haplotype analysis provided a better basis for evaluating the interaction between genetic polymorphisms and cervical carcinogenesis risk. Prior studies of the MTHFR haplotype and cervical cancer were limited to only two candidate polymorphisms (C655T and A1298C) [14,32]. In the present study, Hap3 showed a significant association with CIN1.…”

“…In contrast, two studies reported the MTHFR C677T polymorphism to be an increased risk factor for CIN with the T allele [17,18]. On the other hand, Zoodsma et al [14] reported that the MTHFR C677T genotype is associated with a decreased risk of cervical cancer in women carrying at least one T allele, whereas no association was seen with CIN. …”

“…Genetic variants of these genes alter their respective enzyme activities [4,[8][9][10][11], with consequent abnormalities in DNA methylation and synthesis, and therefore influence susceptibility to cancer [4]. Most studies of cervical cancer have focused on two putative functional polymorphisms in MTHFR C677T and A1298C; however, the findings are inconsistent [12][13][14][15][16][17][18]. Variations in other genes in the one-carbon metabolic pathway could affect cervical cancer risk, but have been evaluated less thoroughly in published studies [15,19].…”

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

“…It is worthwhile to look at the possible interaction between alcohol drinking, cigarette smoking and MTHFR. Thirdly, MTHFR C667T has also been associated in several reports with an increased risk of invasive cervical cancer and premalignant lesions [21], which also indicate a possible role of MTHFR in viral infection associated cancers. Further, MTHFR C677T polymorphism is associated with hype-rhomocysteinemia among patients with chronic hepatitis C infection [22], which may accelerate the progression of liver fibrosis in CHC and possibly lead to liver cancer.…”

Methylenetetrahydrofolate Reductase C677T Polymorphism and Cervical Cancer Risk: a Meta-Analysis

“…After discarding those which clearly did not meet the criteria, 19 studies were further assessed for eligibility (Piyathilake et al, 2000;Goodman et al, 2001;Gerhard et al, 2003;Lambropoulos et al, 2003;Sull et al, 2004;Kang et al, 2005;Zoodsma et al, 2005;Delgado-Enciso et al, 2006;Rao et al, 2006;Piyathilake et al, 2007;Nandan et al, 2008;Shekari et al, 2008;Agodi et al, 2010;Kohaar et al, 2010;Tong et al, 2010;Mostowska et al, 2011;Prasad and Wilkhoo, 2011;Tong et al, 2011;von Keyserling et al, 2011). After reviewing each original paper and extracting data, nine studies were excluded including five studies focusing on cervical intraepithelial neoplasia (Piyathilake et al, 2000;Goodman et al, 2001;Lambropoulos et al, 2003;Piyathilake et al, 2007;Agodi et al, 2010), three studies for not specifying genotypic frequencies of CC, CT, and TT (Gerhard et al, 2003;Nandan et al, 2008;Rao et al, 2006) and one study for overlapping data (Tong et al, 2010).…”