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

Abstract

The purpose of the study was to investigate the association between cervical cancer risk and single-nucleotide polymorphisms (SNPs) in three one-carbon metabolism genes, methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) in Korean women. Twelve SNPs were identified in MTHFR, MTR, and MTRR in the 927 casecontrol samples, which included 165 cervical intraepithelial neoplasia 1 (CIN1), 167 cervical intraepithelial neoplasia 2 and 3 (CIN2/3), 155 cervical cancer patients, and 440 normal controls. The frequencies of the genotypes and haplotypes were assessed in the controls, CINs, and cervical cancers. Individual carriers of the variant allele C of MTHFR A1298C (rs1801131) had a 0.64-fold [95% confidence interval (CI): 0.42-0.98] decreased risk for CIN2/3 compared with common homozygotes. However, no significant association was found between most other variants and cervical cancer risk. The results also identified an increased CIN1 risk in carriers with at least one copy of haplotype 3 in the MTHFR gene (odds ratio, 1.88; 95% CI: 1.03-3.42). In conclusion, there was no significant association between most SNPs in MTHFR, MTR, or MTRR and the risk of CIN and cervical cancer in Korean women. In addition, there was no significant association of MTHFR haplotypes with risk of CIN2/3 and cervical cancer.

Association between MTHFR C677T, MTHFR A1298C and MS A2756G polymorphisms and risk of cervical intraepithelial neoplasia II/III and cervical cancer: A meta-analysis

“…Particularly, the effect of MTHFR and MS polymorphisms on the risk of CIN II/III and cervical cancer also remains inconsistent (12,(15)(16)(17)(18)(19)(20). The MTHFR C677T gene variant has been associated with a risk of cervical carcinogenesis in certain cohorts (13,17,21,23), while this MTHFR gene variant has been associated with protection against CIN II/III or cervical cancer (15), or has not been confirmed as a risk factor for this type of cancer in (3,9,11,23,24,35). Similarly, the influence of MS A2756G polymorphism on the susceptibility of cervical tumorigenesis also remains controversial (11,15,23).…”

“…The MTHFR C677T gene variant has been associated with a risk of cervical carcinogenesis in certain cohorts (13,17,21,23), while this MTHFR gene variant has been associated with protection against CIN II/III or cervical cancer (15), or has not been confirmed as a risk factor for this type of cancer in (3,9,11,23,24,35). Similarly, the influence of MS A2756G polymorphism on the susceptibility of cervical tumorigenesis also remains controversial (11,15,23). Therefore, a systematic meta-analysis with regard to the three most investigated polymorphisms of MTHFR (C677T and A1298C) and MS (A2756G) genes is needed in order to determine the influence of MTHFR or MS polymorphisms on susceptibility to CIN II/III or cervical cancer.…”

“…Two common mutations in the MTHFR gene are C677T and A1298C, and the common variant in MS is an A-to-G transversion at position 2756 (MS A2756G) (9,10). Genetic variants of MTHFR and MS genes modify the activities or other kinetic properties of the encoded enzymes (11). The functional consequences of variant enzyme properties may include abnormalities in DNA synthesis, repair and methylation, and, thereby, altered susceptibility to precancerous lesions and cervical cancer (11).…”

“…However, controversy remains concerning the role of these polymorphisms in cervical carcinogenesis in terms of cancer sites, racial differences and the combined influences of additional risk factors (1,(11)(12)(13)(14)(15)(16)(17)(18). To address such questions, we performed a meta-analysis of published studies to determine potential associations between MTHFR (C677T and A1298C) and MS gene polymorphisms (A2756G) with the risk of CIN II/III and cervical 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). Finally, 10 casecontrol studies with a total of 2113 cervical cancer cases and 2804 controls were included into this meta-analysis (Sull et al, 2004;Kang et al, 2005;Zoodsma et al, 2005;Delgado-Enciso et al, 2006;Shekari et al, 2008;Kohaar et al, 2010;Mostowska et al, 2011;...…”