5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites.

We evaluated polymorphisms in methylenetetrahydrofolate reductase (MTHFR), folate intake and alcohol consumption in relation to risk of colon cancer in a population-based case-control study in North Carolina. The study included 555 cases (244 African Americans and 311 whites) and 875 controls (331 African Americans and 544 whites). Total folate intake of <400 versus > or =400 microg/day showed a weak positive association with colon cancer among both African Americans [adjusted odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.0-2.0] and whites (OR = 1.6, 95% CI = 1.2-2.2). No association was observed with use of alcohol. Compared with wild-type genotypes, there was no association between the low activity MTHFR codon 677 TT genotype and colon cancer, but the low activity codon 1298 CC genotype was inversely associated with colon cancer in whites (OR = 0.5, 95% CI = 0.3-0.9). Unlike previous studies, we did not observe a strong protective effect of the codon 677 TT low-activity genotype when folate intake was high. Instead, we observed an increased risk of colon cancer when folate intake was low for participants with wild- type genotypes. Adjusted ORs for the combined effects of codon 677 CC and codon 1298 AA genotypes and folate intake <400 microg/day were 1.9 (95% CI = 1.1-3.4) in African Americans and 2.5 (95% CI = 1.2-5.2) in whites. Our results suggest that variation at MTHFR codon 1298 (within the COOH-terminal region) may be more important for colon cancer than variation at codon 677 (NH(2)-terminal region), and in populations where folate intake is low, wild-type MTHFR activity may increase risk for colon cancer.     

MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer.

5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5-1.0; women: OR, 0.8, 95% CI, 0.5-1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4-0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5-0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B(2), B(6), B(12), and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = <.01). In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation.     

Folate metabolism-related gene polymorphisms and susceptibility to primary liver cancer in North China

Genetic factors may contribute to individual differences in cancer susceptibility. This study was designed to investigate the effects of the polymorphisms of methylenetetrahydrofolate reductase 677 C → T (MTHFR 677 C → T), methylenetetrahydrofolate reductase 1298 A → C (MTHFR 1298A → C), thymidylate synthase (TYMS 3R → 2R), and methionine synthase 2756 A → G (MTR 2756 A → G) on the risk of primary liver cancer (PLC). We conducted a case-control study involving 356 PLC cases and 641 healthy controls in North China. Compared with the MTHFR 677CC genotype, the MTHFR 677TT genotype showed an increased risk for PLC (TT vs. CC: adjusted odds ratio (OR) = 1.56; 95% confidence interval (CI): 1.02-2.40; P = 0.043) after adjusting for gender and age, whereas the MTHFR 1298CC genotype showed a significantly decreased risk for PLC (CC vs. AA: adjusted OR = 0.23; 95% CI: 0.08-0.70; P = 0.010). However, no significant association was found between the TYMS 3R → 2R or the MTR 2756 A → G polymorphism and the risk of PLC. Our results suggest that the MTHFR 677 C → T and the MTHFR 1298A → C genetic polymorphisms might play important role in hepatic carcinogenesis. Further studies with larger sample sizes are required to validate this association.     

Allele and Genotype Frequencies of the Polymorphic Methylenetetrahydrofolate Reductase and Lung Cancer in ther Jordanian Population: a Case Control Study

Background: Methylenetetrahydrofolate reductase (MTHFR) is involved in amino acid synthesis and DNAfunction. Two common polymorphisms are reported, C677T and A1298C, that are implicated in a number ofhuman diseases, including cancer. Objective: The association between MTHFR C677T and A1298C genotype andhaplotype frequencies in risk for lung cancer (LC) was investigated in the Jordanian population. Materials andMethods: A total of 98 LC cases were studied for MTHFR C677T and A1298C polymorphisms, compared to 89controls taken from the general population, employing the PCR-RFLP technique. Results: The frequency of thegenotypes of MTHFR C677T among Jordanians was: CC, 59.6%, CT, 33%; and TT, 7.4% among LC cases and49.4%, 40.2% and 10.3% among controls. No significant association was detected between genetic polymorphismat this site and LC. At MTHFR A12987C, the genotype distribution was AA, 29.5%; AC, 45.3%, and CC 25.3%among LC cases and 36.8%, 50.6% and 12.6% among controls. Carriers of the CC genotype were more likelyto have LC (OR=2.5; 95%CI: 1.04-6; p=0.039) as compared to AA carriers. Smokers and males with the CCgenotype were 9.9 and 6.7 times more likely to have LC, respectively (ORsmokers=9.9; 95%CI: 1.2-84.5, p=0.018;ORmen=6.6; 95%CI: 1.7-26.2, p=0.005). Haplotype analysis of MTHFR polymorphism at the two loci showeddifferential distribution of the CC haplotype (677C-1298C) between cases and controls. The CC haplotypewas associated with an increased risk for lung cancer (OR=1.6; 95% CI: 1.03-2.4, p=0.037). Conclusions: Thegenetic polymorphism of MTHFR at 1298 and the CC haplotype (risk is apparently lower with the C allele atposition 677) may modulate the risk for LC development among the Jordanian population. Risk associated withthe 1298C allele is increased in smokers and in males. The results indicate that a critical gene involved in folatemetabolism plays a modifying role in lung cancer risk, at least in the Jordanian population.     

Allele and Genotype Frequencies of the Polymorphic Methylenetetrahydrofolate Reductase and Colorectal Cancer among Jordanian Population

Background: Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA synthesis and repair. We hereaimed to investigate two common polymorphisms, C677T and A1298C, with genotype and haplotype frequenciesin colorectal cancer (CRC) cases among Jordanian. Materials and Methods: 131 CRC cases were studied forMTHFR C677T and A1298C polymorphisms, compared to 117 controls taken from the general population,employing the PCR-RFLP technique. Results: We found the frequency of the three different genotypes of MTHFRC677T among Jordanians to be CC: 61.7%, CT: 35.2%, and TT 3.1% among CRC cases and 50.9%, 38.8% and10.3% among controls. Carriers of the TT genotype were less likely to have CRC (OR=0.25; 95%CI: 0.076-0.811;p=0.021) as compared to those with the CC genotype. Genotype analysis of MTHFR A12987C revealed AA:38.9%, AC: 45%, and CC 16% among CRC cases and 37.4%, 50.4% and 12.2% among controls. There wasno significant association between genetic polymorphism at this site and CRC. Haplotype analysis of MTHFRpolymorphism at the two loci showed differential distribution of the TA haplotype (677T-1298A) between casesand controls. The TA haplotype was associated with a decreased risk for colorectal cancer (OR=0.6; 95% CI:0.4-0.9, p=0.03). Conclusions: The genetic polymorphism of MTHFR at 677 and the TA haplotype may modulatethe risk for CRC development among the Jordanian population. Our findings may reflect an importance of genesinvolved in folate metabolism in cancer risk.     

The MTHFR 1298A>C polymorphism and genomic DNA methylation in human lymphocytes.

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.     

Methylenetetrahydrofolate reductase polymorphisms and risk of squamous cell carcinoma of the head and neck: a case-control analysis

Folate deficiency is implicated in cancer risk that may be modulated by a genetic variation in the methylenetetrahydrofolate reductase (MTHFR) gene in folate metabolism. We hypothesized that genetic variants in MTHFR are associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We genotyped 3 MTHFR polymorphisms (C677T, A1298C and G1793A) and estimated their haplotypes in a hospital-based case-control study of 537 SCCHN cases and 545 cancer-free controls. The controls were frequency-matched to the cases by age (+/- 5 years), sex, ethnicity and smoking status. We found that the MTHFR 1298AC/CC genotypes were associated with an approximately 35% reduction in risk of SCCHN (adjusted odds ratio = 0.65; 95% CI = 0.51-0.82) compared to the AA genotype. The MTHFR 677CT and 1793GA/AA genotypes were associated with nonsignificant increased risk of SCCHN compared to the 677CC and 1793GG genotypes, respectively. We estimated that there were 8 haplotypes and 16 haplotype genotypes based on these 3 variants. When we used the haplotypes and assumed that the 677T, 1298A and 1793A alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0-1 variant, 1.85 (1.3-2.5) for any 2 risk alleles and 1.93 (1.4-2.7) for any 3 risk alleles. These results suggest that all 3 MTHFR polymorphisms may play a role in the susceptibility to SCCHN among non-Hispanic whites. Future studies should incorporate detailed data on alcohol consumption, dietary folate intake and related serologic measurements.     

Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. Because germ-line mutations at nucleotides 677 (C-->T) and 1298 (A-->C) in the MTHFR gene cause diminished enzyme activity, and aberrant DNA methylation is oncogenic, we examined the relationship between these two MTHFR polymorphisms and susceptibility to esophageal squamous cell carcinoma (ESCC) in 240 ESCC cases and 360 age- and sex-matched controls in northern CHINA: We found that the allele frequency of MTHFR 677T was significantly higher among cases than among controls (63% versus 41%, P < 0.001). Subjects with the 677TT genotype had a more than 6-fold increased risk of developing ESCC [adjusted odds ratio (OR), 6.18; 95% confidence interval (CI), 3.32-11.51] compared with those who had the 677CC genotype. Furthermore, the elevated ESCC risk associated with the 677 polymorphism was in an allele-dose relationship (trend test, P = 0.0001) with ORs of 1.00, 3.14 (95% CI, 1.94-5.08), and 6.18 (95% CI, 3.32-11.51) for the CC, CT, and TT genotype, respectively, after adjustment for age, sex, smoking status, and the MTHFR 1298 polymorphism. The allele frequency for the MTHFR 1298C was 14% among cases and 17% among controls. The 1298CC genotype was extremely rare in both controls (1.4%) and cases (2.9%) and was also associated with an elevated risk of ESCC (adjusted OR, 4.43; 95% CI, 1.23-16.02) compared with the 1298AA genotype, whereas the 1298AC genotype had no effect on the risk of ESCC. Thus, our findings support the hypothesis that genetic polymorphisms in the MTHFR gene may contribute to susceptibility to carcinogenesis of the esophagus in the at-risk Chinese population.     

MTHFR多态性对晚期胃癌患者化疗作用的预测研究

目的:研究亚甲基四氢叶酸还原酶(MTHFR)基因C677T、A1298C多态与胃癌患者对5-FU为基础的化疗敏感性和毒性的关系。方法:晚期胃癌患者106例,用聚合酶链反应-限定性片段长度多态性(PCR-RFLP)技术检测白细胞DNAMTH-FR基因型。所有患者经5-FU为基础的化疗方案治疗。结果:1)在106例晚期胃癌患者中,MTHFRC677TCC、CT、TT基因型分别占31·1%、46·2%和22·6%;MTH-FRA1298CAA、AC、CC基因型者分别为69·8%、29·2%和0·9%;化疗总有效率35·8%。2)MTHFRC677TTT基因型携带者化疗有效率(83·3%)明显高于C677TCT(24·5%;P=0·000)和C677TCC(18·2%;P=0·000)。而MTHFRA1298CAA组有效率(43·2%)亦明显高于A1298CAC CC组(18·8%,P=0·009)。3)在CFL、CFH、LFP方案治疗的患者中,C677T变异子携带者对化疗敏感性更高。对A1298C多态性,患者接受CFL方案化疗时,1298AA纯合子携带者有效率高于1298CT/CC患者。4)MTHFRC677TTT、CT或A1298CAA多态性携带者化疗相关的恶心/呕吐发生率明显高于其他三种多态性者。结论:MTHFR基因多态性的检测可能是晚期胃癌患者接受5-FU为基础化疗疗效和毒副反应的良好预测指标。     

亚甲基四氢叶酸还原酶基因单核苷酸多态与乳腺癌风险

目的 内研究亚甲基四氢叶酸还原酶(MTHFR)基因单核苷酸多态与女性乳腺癌风险的关系。方法 以聚合酶链反应(PCR)和限制性片段长度多态性(RFLF)分析方法,检测了217例乳腺癌患者和218例配对的正常对照者MTHFR因C677T和A1298C基因型,并比较不同基因型与乳腺癌风险的关系。结果 677TT基因型频率在乳腺癌患者和正常对照中的分布差异有显著性(32．7％比24．8％,P=0．02)。携带MTHFR 677TT基因犁者与携带MTHFR 677CC基因型者比较,前者罹患乳腺癌的风险增加1,84倍(95％ C：1．09～3．14)。MTHFR 677CT基因型以及MTHFR A1298C多态与乳腺癌风险不相关。结论 MTHFR基因677C→T突变是女性乳腺癌的遗传易感因素。     

Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men

We performed a case-control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were frequency-matched to the cases by age (± 5 years), ethnicity, and smoking status. We also measured serum levels of total homocysteine (tHcy), folate, and vitamin B12. It was found that the 1298AC (odds ratio, OR = 3.74; 95% confidence interval, CI = 2.34-5.47; P = 0.001) and 1298CC (OR = 3.46, 95% CI = 2.37-5.52; P = 0.001) genotypes of MTHFR A1298C were significantly associated with increased risk of bladder TCC. The MTHFR C677T and G1793A polymorphisms were not associated with bladder TCC. After stratification for grade and stage, we observed that the 677TT (OR = 4.47, 95% CI = 2.74-6.72; P = 0.001) and MTHFR 1298CC (OR = 4.78, 95% CI = 2.82-6.89; P = 0.001) genotypes of MTHFR were associated with increased risk of muscle-invasive bladder TCC. We also found that the MTHFR 677CT+1298AA genotypes were associated with an approximately 70% reduction in risk of bladder cancer (OR = 0.31; 95% CI = 0.15-0.68) compared to the combined referent genotype. There were 8 haplotypes and 16 haplotype genotypes based on these three variants. When we used the haplotypes and assumed that the 677T, 1298C, and 1793G alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0-1 variant, 1.88 (1.4-2.7) for any two risk alleles and 2.07 (1.6-2.8) for any three risk alleles. Serum tHcy levels were significantly higher in carriers of the 677T, 1298C, and 1793G alleles compared to noncarriers (all P < 0.01). There was no significant correlation between serum levels of tHcy and folate and bladder cancer risk. Further studies in larger samples size and different ethnicity are required to confirm our findings.     

Sex differences in risk of lung cancer associated with methylene-tetrahydrofolate reductase polymorphisms.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides needed for DNA synthesis and repair. Variations in MTHFR functions likely play roles in the etiology of lung cancer. The MTHFR gene has three nonsynonymous single nucleotide polymorphisms (i.e., C677T, A1298C, and G1793A) that have a minor allele frequency of >5%. We investigated the associations between the frequencies of MTHFR variant genotypes and risk of lung cancer in a hospital-based case-control study of 1,051 lung cancer patients and 1,141 cancer-free controls in a non-Hispanic White population. We found that compared with the MTHFR 1298AA genotype, the 1298CC genotype was associated with a significantly increased risk of lung cancer in women [(odds ratio (OR), 2.09; 95% confidence interval (95% CI), 1.32-3.29)] but not in men (OR, 0.95; 95% CI, 0.62-1.45). The MTHFR 677TT genotype was associated with a significantly decreased risk of lung cancer in women (OR, 0.60; 95% CI, 0.40-0.92) but not in men. No association was found between the MTHFR G1793A polymorphism and risk of lung cancer. Further analysis suggested evidence of gene-dietary interactions between the MTHFR C677T polymorphism and dietary intake of vitamin B6, vitamin B12, and methionine in women and evidence of gene-environment interactions between the MTHFR C677T and A1298C polymorphisms and tobacco smoking in men. In conclusion, the polymorphisms of MTHFR may contribute to the risk of lung cancer in non-Hispanic Whites and modify the risk associated with the dietary and environmental exposure in a sex-specific manner.     

Polymorphisms of methylenetetrahydrofolate reductase are associated with a high risk of nasopharyngeal carcinoma in a smoking population from southern China

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in converting folate to a compound which serves as a methyl donor for DNA methylation, an epigenetic modification known to be dysregulated in carcinogenesis. This case–control study assessed the contribution of MTHFR polymorphisms to the risk of nasopharyngeal carcinoma (NPC). MTHFR genotypes C677T and A1298C in 529 NPC patients and 577 frequency‐matched controls were determined by PCR‐based restriction fragment length polymorphism. We found a 1.57‐fold increased risk of NPC in subjects with the MTHFR 1298AC genotype compared to subjects with the MTHFR 1298AA genotype. In addition, an elevated NPC risk was also found in subjects with both the MTHFR 677CT and 1298AC genotypes [odds ratio (OR) = 2.15, 95% confidence interval (CI) = 1.37–3.39] compared to subjects with the 677CC/1298AA genotypes. Furthermore, we observed an additive interaction between MTHFR polymorphisms and smoking status on the increased risk of NPC. The OR was 6.72 (95% CI = 1.85–24.48) among heavy smokers (pack‐years ≥15) carrying 677TT compared with nonsmokers carrying the 677CC genotype. The OR was 7.23 (95% CI = 4.22–12.38) or 12.75 (95% CI = 2.74–59.3) among subjects carrying the 1298AC or 1298CC genotype in heavy smokers (pack‐years ≥15) compared with 1298AA in nonsmokers. Our results provide the first molecular epidemiological evidence that MTHFR polymorphisms associate with the risk of NPC and this association is especially noteworthy in heavy smokers. © 2010 Wiley‐Liss, Inc.     

Associations between methylenetetrahydrofolate reductase polymorphisms and hepatocellular carcinoma risk in Chinese population

Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene are considered to have some influence on both folate metabolism and cancer risk. Previous studies on the associations of MTHFR genetic polymorphisms with hepatocellular carcinoma (HCC) risk in Chinese population reported inconsistent results. We performed this meta-analysis to comprehensively assess the associations. Finally, 12 individual case–control studies were included into the meta-analysis. There were seven studies (6,384 subjects) on the MTHFR C677T polymorphism and five studies (4,502 subjects) on the MTHFR A1298C polymorphism. Overall, MTHFR C677T polymorphism was significantly associated with susceptibility to HCC in Chinese population (T versus C, odds ratio (OR)?=?1.09, 95 % confidence interval (95 % CI) 1.01–1.17; TT versus CC, OR?=?1.17, 95 % CI 1.00–1.38; TT/CT versus CC, OR?=?1.12, 95 % CI 1.00–1.26). MTHFR A1298C polymorphism was conversely associated with HCC risk in Chinese population (CC versus AA, OR?=?0.65, 95 % CI 0.46–0.91; CC versus AA/AC, OR?=?0.64, 95 % CI 0.46–0.90). The sensitivity analysis confirmed the reliability and stability of the meta-analysis. Thus, the findings from our meta-analysis support the associations of MTHFR C677T and A1298C polymorphisms with HCC risk in Chinese population.     

5,10-methylenetetrahydrofolate reductase 677 and 1298 polymorphisms, folate intake, and microsatellite instability in colon cancer.

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a critical role in folate metabolism. Studies on the association between MTHFR polymorphisms and length changes in short tandem repeat DNA sequences [microsatellite instability (MSI)] are inconsistent. Using data from colon cancer cases (n=503) enrolled as part of an existing population-based case-control study, we investigated the association between MTHFR 677 and MTHFR 1298 polymorphisms and MSI. We also examined whether the association was modified by folate intake. Participants were case subjects enrolled as part of the North Carolina Colon Cancer Study. Consenting cases provided information about lifestyle and diet during in-home interviews as well as blood specimens and permission to obtain tumor blocks. DNA from normal and tumor tissue sections was used to determine microsatellite status (MSI). Tumors were classified as MSI if two or more microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250) had changes in the number of DNA sequence repeats compared with matched nontumor tissue. Tumors with one positive marker (MSI-low) or no positive markers (microsatellite stable) were grouped together as non-MSI tumors (microsatellite stable). MTHFR 677 and MTHFR 1298 genotypes were determined by real-time PCR using the 5' exonuclease (Taqman) assay. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (95% CI). MSI was more common in proximal tumors (OR, 3.8; 95% CI, 1.7-8.4) and in current smokers (OR, 4.0; 95% CI, 1.6-9.7). Compared with MTHFR 677 CC referent, MTHFR 677 CT/TT genotype was inversely associated with MSI among White cases (OR, 0.36; 95% CI, 0.16-0.81) but not significant among African Americans. Although not statistically significant, a similar inverse association was observed between MTHFR 677 CT/TT genotype and MSI among the entire case subjects (OR, 0.54; 95% CI, 0.26-1.10). Among those with adequate folate intake (>400 microg total folate), we found strong inverse associations between combined MTHFR genotypes and MSI (677 CC+1298 AC/CC, OR, 0.09; 95% CI, 0.01-0.59; 677 CT/TT+1298 AA, OR, 0.13; 95% CI, 0.02-0.85) compared with the combined wild-type genotypes (677 CC+1298 AA). This protective effect was not evident among those with low folate (<400 microg total folate) intake. Our results suggest that MTHFR variant genotypes are associated with reduced risk of MSI tumors under conditions of adequate folate intake, although the data are imprecise due to small numbers. These results indicate that the relationship between MTHFR genotypes and MSI is influenced by folate status.     

Polymorphisms in the DNA methyltransferase 3b gene and prostate cancer risk

Inactivation of tumor suppressor genes by promoter methylation is an important mechanism of tumorigenesis. Increased expression of DNA methyltransferases has been commonly observed in cancer. A C/T polymorphism in the DNA methyltransferase 3b (DNMT3b) promoter region results in increased activity and has recently been identified as a risk factor for lung cancer. In this study, we examined the C/T polymorphism of the DNMT3b gene in specimens from 81 patients with prostate cancer and 42 controls selected from patients with benign prostatic hypertrophy (BPH). Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. DNMT3b genotypes were determined by restriction-fragment-length-polymorphism polymerase chain reaction. The DNMT3b polymorphism frequencies in the prostate cancer and BPH specimens were, respectively, 20 and 26% for CC, 42 and 52% for CT, and 38 and 21% for TT. Although such differences fall within the realm of chance variation (P>0.05), the data suggest that the TT genotype may be associated with an increased risk of prostate cancer: the age-adjusted odds ratio (aOR) was 2.6 [95% confidence interval: 0.8-8.0]; the increase in odds ratio was seen in both blacks and whites (aOR=4.3 in blacks, and 2.0 in whites). The samples used in this study have previously been examined for methylation index (MI) based on the number of genes methylated, the range being 0 to 5. A trend toward an increase in MI was detected for the DNMT3b polymorphisms in prostate cancer patients but not for BPH subjects (mean MI 2.6, 2.9, 3.1 for CC, CT, and TT genotype in prostate cancer; 0.8, 0.8, 0.7 for CC, CT, and TT genotype in BPH subjects). These findings suggest that the DNMT3b polymorphisms may be associated with an increase in promoter methylation of tumor-suppressor genes related to the development of prostate cancer, and may thereby increase the risk of this disease.     

Polymorphisms of methylene-tetrahydrofolate reductase and risk of lung cancer: a case-control study.

Previous studies have suggested that low folate intake is associated with increased risk of lung cancer. Methylene-tetrahydrofolate reductase (MTHFR) is one of the enzymes involved in folate metabolism and is thought to influence DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. Therefore, we hypothesized that these variant genotypes may play a role in the etiology of lung cancer. To test this hypothesis, we investigated the association between two common MTHFR polymorphisms (C677T and A1298C) and risk of lung cancer in a non-population-based case-control study of 550 histologically confirmed lung cancer cases and 554 healthy controls. The subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (+ or -5 years), sex, and smoking status (ever or never). Folate intake and alcohol consumption were estimated from a self-administered food-frequency questionnaire. The cases consumed significantly less folate (162 microg/day/1000 kcal) than the controls did (172 microg/day/1000 kcal; P = 0.033). However, we found no evidence for an association between the MTHFR C677T and A1298C polymorphisms and risk of lung cancer in either all of the subjects or the low folate intake subgroup; nor did we find evidence for an interaction between these two MTHFR polymorphisms and dietary folate intake or alcohol use. In multivariate logistic regression analysis, the adjusted odds ratios and 95% confidence intervals for MTHFR C677T were 1.1 (0.8-1.4) for 677CT versus 677CC wild type and 1.1 (0.7-1.7) for 677TT versus 677CC, and for MTHFR A1298C, they were 1.0 (0.8-1.3) for 1298AC versus 1298AA wild type and 1.1 (0.7-1.8) for 1298CC versus 1298AA. These results suggest that the MTHFR C677T and A1298C polymorphisms by themselves do not play an important role in the etiology of lung cancer.     

Relationship between Genetic Polymorphisms in MTHFR (C677T,A1298C and their Haplotypes) and the Incidence Of Breast Cancer among Jordanian Females - Case-Control Study

Background: Breast cancer is a major cause of morbidity and mortality in Jordan and worldwide. Abnormalityof DNA methylation is a possible mechanism for the development of cancer. Methylenetetrahydrofolate reductase(MTHFR) is involved in DNA methylation. Our aim was to study the association between genetic polymorphismsof MTHFR at two sites (C677T and A1298C) and their haplotypes and the risk of breast cancer among Jordanianfemales. Materials and Methods: A case-control study involving 150 breast cancer cases and 150 controlswas conducted. Controls were age-matched to cases. Polymerase chain reaction/restriction fragment lengthpolymorphism (PCR-RFLP) technique and sequencing were conducted to determine the genotypes. Results:There was a significant difference in genotype frequency of C677T in the 41-60 year age category [cases: CC(37.4%), CT (49.5%) and TT (13.2%); controls: CC (56.3%), CT (35.6%) and TT (8%), p= 0.04; ORTT vs. CC: 2.5,95% CI: (0.9-6.9); ORat least on T: 2.1, 95%CI: (1.2-3.9)]. There was no significant difference in genotype frequencyof A1298C between cases and controls [cases: AA (46.6%), AC (41.8%) and CC (11.6%); controls: AA (43%),AC (47.4%) and CC (9.6%); p= 0.6]. There was a significant difference of MTHFR genetic polymorphismhaplotypes among breast cancer cases and controls [cases/control: CA: 38.3/45.4%; CC: 28.9/25.2%; TA: 29.2/21;TC: 3.6/8.3; p value= 0.01; ORTA vs. CA= 1.6; 95% CI (1.1-2.5); p= 0.02]. Conclusions: Genetic polymorphism ofMTHFR C677T may modulate the risk of breast cancer especially in the 41-60 year age group. Additionally, TAhaplotype amends the risk of breast cancer. Future studies with a larger sample size are needed to validate therole of MTHFR genetic polymorphisms in breast cancer.     

Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women

Dietary folate status as well as polymorphisms in one-carbon metabolism genes may affect the risk of breast cancer through aberrant DNA methylation and altered nucleotide synthesis and DNA repair. A large number of studies investigated the role of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms in breast cancer with inconsistent results. Association between multiple polymorphisms in one-carbon metabolism genes and breast cancer was not studied before in an Arab population. The purpose of the present study is to test the hypothesis that polymorphisms in one-carbon metabolism genes are associated with breast cancer susceptibility in Syrian breast cancer women patients. A total of 245 subjects (119 breast cancer women patients and 126 healthy controls) were genotyped for MTHFR C677T and A1298C and MTRR A66G polymorphisms. Association was tested for under numerous genetic models. A statistically significant association was found for MTHFR A1298C polymorphism especially under the allele contrast model (odds ratio (OR) = 1.68, 95% confidence interval (CI) (1.16-2.45), P = 0.006). On the other hand, no significant association was found for MTHFR C677T or MTRR A66G under any of the genetic models tested. The effects of the compound genotypes were also examined. The 66GG genotype was found to be protective against breast cancer when combined with the 677CT or 1298AC genotype (OR = 0.18, 95% CI (0.04-0.82), P = 0.014; OR = 0.3, 95% CI (0.08-1.11), P = 0.058). In conclusion, our study supports the hypothesis that polymorphisms in one-carbon gene metabolisms modulate the risk for breast cancer, particularly the A1298C polymorphism of the MTHFR gene.