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。     

Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer

Authors report the results of four meta-analyses of studies that examined the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and head and neck cancer (nine studies, 2076 cases and 4834 controls for C677T; four studies, 1439 cases and 3941 controls for A1298C), and lung cancer (ten studies, 5274 cases and 7435 controls for C677T; seven studies, 5098 cases and 6243 controls for A1298C). The summary odds ratio (OR) of head and neck cancer was 0.92 (95% CI: 0.76–1.11) for MTHFR 677 TT and 0.68 (95% CI: 0.37–1.26) for MTHFR 1298 CC. The OR of lung cancer was 1.22 [95% confidence interval (CI): 0.95–1.55] for MTHFR 677 TT and 1.07 (95% CI: 0.83–1.38) for MTHFR 1298 CC. Results from the meta-analysis of three studies on C677T stratified according to dietary folate intake showed an increased risk for individuals with low folate intake (OR = 1.37, 95% CI: 0.92–2.06 for head and neck and OR = 1.28, 95% CI: 0.97–1.68 for lung) versus high folate intake (OR = 0.85, 95% CI: 0.63–1.16 for head and neck, and OR = 0.94, 95% CI: 0.79–1.12 for lung). Despite the lack of formal statistical significance, these findings are consistent with the hypothesis that folate play a role in lung and head/neck carcinogenesis, and show the need to incorporate data on folate intake when interpreting results of MTHFR polymorphisms in relation to cancer risk.     

MTHFR基因C677T和A1298C多态性与肺癌的关系

目的:通过对广东地区汉族肺癌患者和正常人群中MTHFRC677T和A1298C基因多态性分布检测,探讨与肺癌之间的关系。方法:研究分肺癌组和正常对照组各100例,分别利用PCR进行两组MTHFR基因多态性的检测。结果:肺癌组和对照组中MTHFRC677T各基因亚型的分布有显著性差异(χ2=7.002,P=0.030),其中CC基因亚型在两组之间的分布有显著性差异(χ2=5.214,P=0.022),CT基因亚型无显著性差异(χ2=0.320,P=0.572),TT基因亚型也有显著性差异(χ2=4.013,P=0.045),而MTHFRA1298C基因多态性分布在肺癌病例与正常人之间的分布无明显变化,统计学上无显著性差异(χ2=0.098,P=0.952)。结论:MTHFR基因C677T在肺癌病例与正常人之间的分布有所不同,有助于从分子遗传学角度发现肺癌的高危人群,从而对人群进行筛选。     

亚甲基四氢叶酸还原酶基因 C677T多态性与胃癌患者对 5-FU化疗敏感性的关系

背景和目的:亚甲基四氢叶酸还原酶( methylenetetrahydrofolate reductase,MTHFR)基因变异影响 MTHFR的活性,以致影响体内 5, 10-MTHF的浓度,从而影响 5-FU的抗瘤活性.本研究旨在观察 MTHFR基因 C677T多态性对预测胃癌患者对 5-FU的敏感性和化疗毒性的影响.方法:收集经病理学确诊的晚期胃癌 75例.所有病例化疗前抽外周静脉血 2 ml,用 PCR-RFLP技术检测研究对象的 MTHFR 基因型.基因型分为野生型纯合子 (C/ C)、杂合子 (C/ T)、变异型纯合子 (T/ T)3种类型.所有患者经含 5-FU为基础的联合化疗方案化疗.结果: 75例晚期胃癌患者中, MTHFR C/ C基因型 24例( 32.0%), MTHFR C/ T基因型 33例( 44.0%), MTHFR T/ T基因型 18例( 24.0%).其中 22例 PR, 29例 NC, 24例 PD,化疗总有效率 29.3%. MTHFR T/ T基因型患者的化疗有效率( 20/24, 83. 3%)明显高于 MTHFR C/ C基因型患者( 2/24, 8. 3%)(χ 2=24. 01, P< 0. 001),同样高于 MTHFR C/ T基因型患者( 5/33, 15. 2%)(χ 2=22. 7, P< 0. 001). MTHFR C/ C基因型患者的化疗有效率与 MTHFR C/ T基因型患者之间无显著性差异(χ 2=0. 6, P=0. 439).非条件多元 Logistic 回归分析(调整性别、年龄、化疗方案、辅助化疗因素的影响)结果显示 C/ C+ C/ T基因型患者对化疗有效的可能性为 T/ T基因型患者的 0. 017倍( 95% CI: 0. 003～ 0. 102,P< 0. 001). T/ T基因型患者的恶心呕吐反应显著高于 C/ C、 C/ T基因型患者(χ 2=12.264,P=0.002).结论: MTHFRC677T基因型对预测以 5-FU为基础化疗方案治疗晚期胃癌的疗效和毒性具有较好的临床意义.     

MTHFR基因1298 A→C多态与新疆哈萨克族食管癌风险关系的研究

目的:探讨亚甲基四氢叶酸还原酶(MTHFR)基因1298A→C多态及其和生活习惯相互作用与新疆哈萨克族食管癌风险的关系。方法:收集经组织病理学确诊的哈萨克族食管鳞癌新发病例88例外周血液标本,提取DNA;72名健康哈萨克族人群作为对照,同时调查每个研究对象的吸烟、饮酒情况。用PCR-RFLP技术检测研究对象的MTHFR1298A→C基因多态性。结果:病例组MTHFR1298AA、AC和CC基因型分别为63.64%、34.09%和2.27%,与对照组的72.22%、27.78%和0相比差异无统计学意义,χ2MH=2.57,P=0.276。MTHFR1298AA、MTHFR1298AC基因型与哈萨克族食管癌的发生无显著相关性,P>0.05。病例组与对照组1298C等位基因频率分别为0.19和0.14,两组间差异无统计学意义,P>0.05。与携带MTH-FR1298AA基因型的不吸烟者相比,携带MTH-FR1298C等位基因且有吸烟习惯者的性别、年龄以及饮酒习惯调整OR值为2.353(95%CI为0.892～6.210)。与携带MTHFR1298AA基因型的不饮酒或不常饮酒者相比,携带MTHFR1298C等位基因并伴有经常饮酒的习惯者发生食管癌的危险性也显著增高,其性别、年龄以及饮酒习惯调整OR值为1.860(95%CI为0.585～5.915)。结论:叶酸摄入不足是新疆哈萨克族食管癌的危险因素;MTHFR1298AC和CC基因型对吸烟、饮酒习惯增加食管癌发生风险作用有放大效应。     

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

Objectives Methylenetetrahydrofolate reductase (MTHFR), which is expressed in the liver, may be involved in both DNA methylation and DNA synthesis. It is also indicated as a potential risk factor of liver cancer in patients with chronic liver disease. To date, no study has been conducted on MTHFR and hepatocellular carcinoma (HCC) using a population-based design. The objective of this study was to evaluate the effects of polymorphisms of the MTHFR gene on the risk of primary liver cancer and their possible effect modifications on various environmental risk factors. Methods A population-based case–control study was conducted in Taixing, China. MTHFR C677T and A1298C were assayed by PCR-RFLP techniques. Results The frequency of MTHFR 677 C/C wild homozygotes genotype was 25.8% in cases, which was lower than that in controls (34.5%). The adjusted odds ratios (ORs) for the MTHFR 677 C/T and T/T genotype were 1.66(95% CI: 1.06–2.61), 1.21(95% CI: 0.65–2.28) respectively when compared with the MTHFR 677 C/C genotype. Subjects carrying any T genotype have the increased risk of 1.55(95% CI: 1.01–2.40) for development of primary hepatocellular carcinoma. A high degree of linkage disequilibrium was observed between the C677T and A1298C polymorphisms, with the D′ of 0.887 and p < 0.01. The MTHFR 677 any T genotype was suggested to have potentially more than multiplicative interactions with raw water drinking with p-value for adjusted interaction of 0.03. Conclusion We observed that the MTHFR 677 C/T genotype was associated with an increased risk of primary liver cancer in a Chinese population. The polymorphism of MTHFR 677 might modify the effects of raw water drinking on the risk of primary hepatocellular carcinoma.     

Influence of methylenetetrahydrofolate reductase gene polymorphisms C677T and A1298C on age-associated risk for colorectal cancer in a caucasian lynch syndrome population.

Lynch syndrome is caused by germ-line mutations in the DNA mismatch repair (MMR) genes; mutation carriers are predisposed to a variety of cancers, most commonly colorectal and endometrial. The median age of colorectal cancer onset is 45 years and the lifetime risk is approximately 80%, but the onset age varies substantially. It is likely that other low-penetrance genes and environmental factors act as modifiers of the risk associated with the highly penetrant MMR gene mutations. Methylenetetrahydrofolate reductase plays a key role in folate metabolism. We investigated the association of C677T and A1298C, two common polymorphisms in the methylenetetrahydrofolate reductase gene, with risk for early onset colorectal cancer in Lynch syndrome. Subjects were 185 non-Hispanic whites with confirmed DNA MMR mutations. Kaplan-Meier estimates for the age at colorectal cancer onset according to C677T genotypes were significantly different for the CT and TT genotypes compared with the wild-type CC (P = 0.014, log-rank test; P = 0.004, trend test). The median ages at onset were 43 years for the CC genotype and 39 years for the combined CC and CT genotypes and the CC+CT genotypes were associated with a reduced age-associated risk for developing colorectal cancer (hazard ratio, 0.55; 95% confidence interval, 0.36-0.85). No differences in ages at onset or risk were found for the A1298C genotypes. This is the first report to our knowledge to provide evidence that the C677T polymorphism modifies the age at onset of colorectal cancer in Caucasian Lynch syndrome subjects with the 677T allele having a protective effect.