亚甲基四氢叶酸还原酶基因多态性检测在肿瘤患者中的临床价值

摘 要：亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase MTHFR)是叶酸代谢、DNA甲基化的关键酶。MTHFR的单核苷酸多态性(single nucleotide polymorphism,SNP),包括677 C→T和1298A→C突变,可使MTHFR酶活性下降,从而影响细胞内叶酸的正常代谢。全文分析MTHFR 基因多态性对叶酸代谢和DNA合成的影响及其在恶性肿瘤发生、诊治和预后的研究进展,阐述恶性肿瘤患者中检测MTHFR基因多态性的价值及存在争议。     

MTHFR基因多态性与结直肠癌的相关性

结直肠癌是全球最常见的恶性肿瘤之一.亚甲基四氢叶酸还原酶(MTHFR)是叶酸代谢的关键酶,近年来许多研究显示其基因多态性与结直肠癌的发病率、相关抗肿瘤药物的疗效及预后相关,但结论尚不完全一致,有待更多临床研究证实.     

叶酸与结直肠肿瘤

流行病学和试验研究提示叶酸缺乏及叶酸代谢异常和结直肠肿瘤发病风险升高有关。亚甲基四氢叶酸还原酶（MTHFR）是调节叶酸代谢的关键酶，MTHFRC677T基因多态及饮酒影响叶酸代谢，从而影响结直肠肿瘤的发病风险。     

亚甲基四氢叶酸还原酶基因多态性与乳腺癌相关性的研究进展

乳腺癌是一种复杂的全身性的疾病,其发病机制尚未完全清楚,但受基因及环境相互作用的影响。亚甲基四氢叶酸还原酶（MTHFR）基因位于1号染色体短臂的末端（1p36.6）,是叶酸代谢途径的关键酶,参与DNA合成、修复及甲基化过程。MTHFR基因多态性的分布在不同的种族及区域存在差异,其基因的单核苷酸突变会使该酶的生物活性及热稳定性下降,参与肿瘤的发生及发展过程,多项研究显示 MTHFR基因多态性与乳腺癌发生、发展及预后密切相关。     

叶酸代谢相关酶基因多态性与消化系统肿瘤的关系

叶酸的主要生物学功能是作为甲基供体参与脱氧核糖核酸合成和细胞内甲基化反应.亚甲基四氢叶酸还原酶(methylene tetrahydrofolate reductase,MTHFR)、甲硫氨酸合成酶(methionine synthase,MTR)、甲硫氨酸合成酶还原酶(methionine synthase reductase,MTRR)、胸苷酸合成酶(thymidylate synthase,TS)和亚甲基四氢叶酸脱氢酶(methylenetetrahydrofolate dehydrogenase,MTHFD)等是叶酸代谢通路中重要的酶.叶酸代谢相关酶基因变异、叶酸缺乏或代谢障碍与肿瘤的发生和发展有关.本文就叶酸代谢相关酶基因多态性与消化系统肿瘤间的关系进行简要综述.     

以铂类为基础治疗非小细胞肺癌的疗效及与MTHFR C677T基因多态性的相关性分析

目的 探讨以铂类为基础治疗非小细胞肺癌的疗效及其与亚甲基四氢叶酸还原酶(MTHFR)C677T基因多态性的相关性.方法 选取经病理确诊行手术切除后接受以铂类为基础化疗方案的NSCLC患者180例为研究组,另选择同期体检的健康人100名作为健康对照组.通过血液学标本提取的DNA进行MTHFR C677T基因分型.比较MT...     

亚甲基四氢叶酸还原酶基因多态性与肺癌易感性的关系

目的研究亚甲基四氢叶酸还原酶(MTHFR)基因多态性与肺癌易感性的关系。方法采用PCRRFLP方法检测MTHFR基因型在广东地区肺癌患者和正常人群中的分布。结果肺癌组和对照组中MTHFR各基因型的分布有显著性差异(P=0.030),在男女两种性别之间,非小细胞肺癌和小细胞肺癌之间,非小细胞肺癌各个病理类型之间,肺癌病例各个临床分期之间MTHFRC677T多态性的分布没有显著性差异。结论MTHFR基因C677T突变在肺癌病例中的分布与正常人群中的分布有明显的差异。     

肺癌患者MTHFR基因多态性与抑癌基因过甲基化的关系

目的：探讨亚甲基四氢叶酸还原酶基因多态性与肺癌易感性及抑癌基因甲基化的关系。方法：采用病例对照研究的方法,以限制性片段长度多态性方法,检测了93例肺癌患者及106例对照的MTHFR C677T基因型;用巢式甲基化特异性PCR（nMSP）法检测肺癌患者外周血血清中p16及MGMT基因的甲基化。结果：MTHFR C677T C/C,C/T,T/T基因型分布频率在病例组中分别为：29%、49.5%、21.5%,在对照组中分别为：36%、51%、19%,频率分布差异无统计学意义。病例组中p16甲基化检出率为68%（63/93）,MGMT甲基化检出率为52%（48/93）。各基因型之间的p16与MGMT基因甲基化阳性率差异无统计学意义（ P >0.05）。结论：MTHFR基因 C677T多态性与肺癌发生之间未发现相关,MTHFR变异基因型（C/T,T/T）并非导致p16与MGMT基因甲基化的直接原因。     

云南人亚甲基四氢叶酸还原酶基因型多态性与乳腺癌易感性的关联

 目的亚甲基四氢叶酸还原酶(MTHFR)是叶酸代谢的关键性酶,其催化作用决定了DNA甲基化与DNA合成之间的平衡。MTHFR基因多态性可能会影响叶酸代谢结局,从而构成肿瘤风险因子。研究分析了MTHFR各基因型在云南籍乳腺癌人群和正常人群中的分布差异,初步探索了MTH-FR多态性与乳腺癌易感性之间的关系。方法以多重PCR-RFLP技术,对125例云南籍乳腺癌患者和103例正常人群MTHFR677位点1298位点多态性进行筛查。结果未发现MTHFRC677T和A1298C基因型频率在乳腺癌和对照样本之间存在显著差异。结论在目前样本条件下,上述两个MTHFR位点基因型多态性与云南籍人群的乳腺癌易感性之间无明显相关性。     

叶酸与肿瘤

叶酸是水果和蔬菜中的重要营养成分之一,其主要生物学功能是作为甲基供体参与细胞内的甲基化反应和脱氧核糖核酸的从头合成。叶酸缺乏与肿瘤的发生有关联,这可能是因为叶酸缺乏影响DNA合成、修复和正常甲基化。叶酸在细胞内需要代谢转化才能发挥其生物学作用。亚甲基四氢叶酸还原酶(methylenetetrahvdrofolate reductase,MTHFR)是叶酸代谢通路中的关键酶,MTHFR基因的单核苷酸多态(677C→T和1298A→C)使其编码的酶功能活性显著降低,从而影响叶酸的生物转化和功能。众多的研究表明,MTHF基因的单核苷酸多态是一些肿瘤的遗传易感性因素。     

Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study

There is substantial evidence that the decreased risk of lung cancer with high intake of vegetables and fruits is linked to folate as a specific nutrient. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T and A1,298C), methionine synthase (MTR A2,756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase, influence folate metabolism and thus might be suspected of impacting on lung cancer risk. We therefore conducted a case-control study with 515 lung cancer cases newly and histologically diagnosed and 1,030 age- and sex-matched non-cancer controls to clarify associations with these five polymorphisms according to lung cancer subtype. Gene-environment interactions with smoking and drinking habit and folate consumption were also evaluated by logistic regression analysis. None of the polymorphisms showed any significant impact on lung cancer overall risk by genotype alone, but on histology-based analysis increase in MTHFR 677T and 1,298C alleles was associated with reduced risk of squamous/small cell carcinoma (P = 0.029), especially among heavy smokers (P = 0.035), whereas the MTHFR 677TT genotype was linked to decreased risk for these subtypes among heavy drinkers (odds ratio = 0.17, 95% confidence interval: 0.03-0.98). In addition, we found interactions between the MTRR A66G polymorphism and smoking (P = 0.015) and the MTHFR A1,298C polymorphism and alcohol consumption (P = 0.025) for risk of lung cancer overall. In conclusion, the results suggest that MTHFR polymorphisms contribute to risk of squamous/small cell carcinomas of the lung, along with possible interactions among folate metabolism-related polymorphisms and smoking/drinking habits. Further evaluation is warranted.     

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.     

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.     

亚甲基四氢叶酸还原酶多态性与乳腺癌化疗敏感性的相关研究

目的:观察叶酸代谢的关键酶亚甲基四氢叶酸还原酶(MTHFR)基因C677T、A1298C多态性与乳腺癌FEC方案化疗敏感性的关系。方法:收集经病理学确诊的初治乳腺癌患者104例,所有病例化疗前抽静脉血,提取DNA,用PCR-RFLP技术检测MTHFR基因型,所有患者行FEC方案新辅助或姑息性化疗2~6周期,比较疗效和基因型之间的关系。结果:104例乳腺癌患者中,MTHFR C677T T/T基因型39例(37.5%)、C/C基因型55例(52.9%)、C/T基因型 10例(9.6%);T/T基因型化疗有效率79.5%(31/39)高于C/C基因型52.7%(29/55)和C/T基因型20.0%(2/10)（P＜0.05）。MTHFR A1298C A/A基因型41例(39.4%),A/C基因型56例(53.8%),C/C基因型7例(6.7%);各基因型化疗有效率之间无统计学关系（P＞0.05）。结论:本研究初步显示MTHFR C677T基因多态性对预测乳腺癌化疗效果具有较好的临床应用价值。     

Folate Pathway Gene MTHFR C677T Polymorphism and Risk of Lung Cancer in Asian Populations

Background: Previous studies concerning the association between the 5,10-methylenetetrahydrofolatereductase (MTHFR) C677T gene polymorphism with lung cancer in Asian populations have provided inconclusivefindings. Aim: A meta-analysis was performed to investigate a more reliable association between MTHFR C677Tpolymorphism and lung cancer in Asians. Materials and Methods: A comprehensive search was conducted toidentify all case-control studies of MTHFR polymorphisms and lung cancer in Asia, using odds ratios (ORs) with95% confidence intervals (CIs) to assess the strength of any association. Results: Meta-analysis results suggestedthat the MTHFR C677T polymorphism contributed to an increased lung cancer risk in Asian populations (forT vs C: OR=1.11, 95%CI=1.0-1.23; for CT vs CC: OR= 1.1, 95%CI= 0.95-1.2 ; for TT+CT vs CC: OR=1.13,95%CI=1.0-1.30; for TT vs CC: OR=1.25, 95%CI=1.01-1.30; for TT vs CT+CC: OR=1.16, 95%CI=1.0-1.36).Conclusions: MTHFR C677T polymorphism is significantly associated with lung cancer in Asians.     

亚甲基四氢叶酸还原酶和胸苷酸合成酶基因多态预测氟尿嘧啶为基础化疗方案治疗晚期胃癌疗效关系的研究

目的观察亚甲基四氢叶酸还原酶（MTHFR）（C677T、A1298C）和胸苷酸合成酶（TS3’-UTR）多态与5-FU为基础化疗方案及晚期胃癌敏感性的关系。方法选取173例晚期胃癌患者,所有病例均接受5-FU为基础化疗方案（FOLFOX,FP和DCF方案）化疗。在化疗前获取外周血白细胞DNA。采用PCR—RELP检测基因型。在2个基因中共检测了9种遗传多态。173例中检测了MTHFR（C677T、A1298C）和TS（3＇-TUR）多态。结果所有患者化疗总有效率为35．8％。DCF方案的有效率显著高于FP和FOLFOX方案（55．8％ vs 27．1％,31．1％;P=0．006）。MTHFRC677TT／T基因型患者的有效率显著高于C／C和C／T基因型（73．3％vs28．0％;P=0．000）。在MTHFRA1298C中,A／A基因型患者的有效率显著高于C／C和A／C基因型（41．8％vs21．6％,P=0．011）。在TS 3＇-UTR中,-6／-6bp和-6/＋6bp基因型患者的有效率显著高于＋6／＋6bp基因型（40．3％vs17．6％,P=0．014）。FOLFOX和FP方案中,MTHFR C677T T／T基因型患者的有效率均显著高于C／C和C／T基因型（P=0．008;P=0．000）,但在DCF方案中没有发现差异。在MTHFRC／T和C／C基因型中,DCF方案的有效率显著高于FP和FOLFOX方案（P=0．000）。MTHFR C677T T／T基因型患者的Ⅲ～Ⅳ度呕吐（66．7％）和口腔炎（30．0％）发生率显著高于C／C和C／T基因型（41．3％,9．8％;P=0．011,0．003）。MTHFRA1298CA／A基因型患者的Ⅲ～Ⅳ°度口腔炎（17．2％）和腹泻（13．9％）发生率同样显著高于A／C和C／C基因（3．9％,2．0％;P=0．025,0．026）。TS 3^＋-UTR的不同多态之间没有发现毒性差异。结论检测外周血白细胞DNA中的MTHFR和TS基因多态能预测以5-FU为基础化疗方案治疗晚期胃癌的有效性和化疗相关的毒性反应。     

基因多态性与FOLFOX方案治疗胃肠癌敏感性的关系

目的研究MTHFR C677T和XRCC1 G28152A基因多态性与接受FOLFOX方案的胃肠癌患者化疗敏感性与毒副反应的关系。方法经FOLFOX方案化疗的进展期胃肠癌48例（22例有临床可观察肿瘤病灶）,化疗前抽外周静脉血2 mL,用PCR-RFLP技术检测研究对象的MTHFR C677T和XRCC1 G28152A基因型。化疗两周期后全面评价疗效及毒副反应,并随访观察进展情况。结果 （1）48例胃肠癌患者,MTHFR 677 C/C、C/T、T/T基因型分别为39.6%、37.5%及22.9%。XRCC1 28152 G/G、G/A、A/A基因型分别为52.1%、45.8%及2.1%。22例可观察肿瘤病灶者MTHFR 677 C/C、C/T、T/T基因型疾病控制率分别为14.2%、66.6%和100.0%,T/T基因型明显高于C/C型（P〈0.05）;XRCC1 28152 G/G、G/A＋A/A基因型疾病控制率分别为90.9%、36.4%,差异有统计学意义（P〈0.05）。（2）48例患者带有MTHFR677 C/C、C/T、T/T基因型的2年无复发生存率分别为21.1%、36.8%和72.7%,T/T基因型明显高于C/C型（P〈0.05）;XRCC1 28152 G/G、G/A＋A/A基因型2年无复发生存率分别为52.0%和21.7%,差异有统计学意义（P〈0.05）。（3）患者接受FOLFOX方案化疗后带有MTHFR 677 C/T、T/T患者恶心/呕吐的发生率（77.8%、81.8%）明显高于C/C基因型患者（26.3%）。XRCC1 28152 G/G、G/A＋A/A基因型恶心/呕吐分别为44.0%,78.3%,差异有统计学意义（P〈0.05）,其余毒副反应与基因型之间差异均无统计学意义（P〉0.05）。结论 MTHFR C677T和XRCC1 G28152A基因多态对胃肠癌接受FOLFOX方案化疗疗效与毒性有良好的提示作用。     

Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China

The aim of this study is to investigate the role of genetic polymorphisms in twelve folate metabolism genes on the risk of lung cancer in Xuan Wei, China, where the lung cancer mortality rate is among the highest and is mainly caused by indoor smoky coal emissions. A total of 122 incident primary lung cancer cases and 122 matched controls were enrolled. Three single nucleotide polymorphisms were associated with increased risk of lung cancer including homozygotes of the C allele of CBS Ala360Ala (OR: 4.02; 95% CI: 1.64-9.87), the 222Val allele of MTHFR (OR: 2.32; 95% CI: 1.34-4.03), and the C allele of SLC19A1 Pro232Pro (OR: 1.83; 95% CI: 1.02-3.28). The distribution of CBS and MTHFR haplotypes differed between cases and controls (P=0.002 and P=0.07, respectively). In summary, three genetic variants in folate metabolism genes are associated with an increased risk of lung cancer in Xuan Wei, China.     

Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan

Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one-carbon metabolism for DNA synthesis and methylation, both are implicated in carcinogenesis. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate cancer-predisposing factor. To evaluate the C677T and A1298C functional polymorphisms in the MTHFR gene and their associations with breast cancer risk, as well as the potential modifying effect by plasma folate status on the MTHFR-associated risk, a hospital-based case-control study was conducted on a Taiwanese population consisting of 146 histologically confirmed incident breast cancer cases and their 285 age-matched controls without a history of cancer. A PCR-RFLP method was used for MTHFR polymorphism genotyping and RIA was used to measure the plasma folate. Statistical evaluations were performed using logistic regression analysis. The plasma folate level was inversely associated with breast cancer risk with an adjusted odds ratio (OR) of 0.52 [95% confidence interval (CI): 0.26-1.05] observed among women who were in the highest plasma folate tertile. The MTHFR 677T and 1298C variant alleles were associated with decreased risk for breast cancer [adjusted ORs were 0.81 (95% CI: 0.54-1.21) and 0.57 (95% CI: 0.36-0.89) for 677CT + TT genotypes and 1298AC + CC genotypes, respectively]. Furthermore, compound heterozygote and homozygote variants (677CT + TT and 1298AC + CC) had greater reduced risk (adjusted OR: 0.11, 95% CI: 0.03-0.43) among women with lower plasma folate levels. These results provide support for the important role of folate metabolism in breast tumorigenesis. Further mechanistic studies are warranted to investigate how MTHFR combined genotypes exert their effect on cancer susceptibility.