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。     

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。     

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。     

东北地区亚甲基四氢叶酸还原酶基因C677T单核苷酸多态性与乳腺癌易感性的相关性研究

目的::研究亚甲基四氢叶酸还原酶(MTHFR)基因单核苷酸多态性与乳腺癌易感性的关系.方法:采用以人群为基础的病例对照研究方法,聚合酶链反应-限制性片段长度多态性法检测MTHFR基因型在东北地区乳腺癌患者和正常人群中的分布.结果:MTHFR基因677位点在乳腺癌组和对照组中等位基因频率及基因型分布有显著差异性(P<0.05).进一步分析表明,纯合突变G/G基因型、杂合突变C/G基因型与野生C/C基因型相比,患乳腺癌的危险度分别提高了2.23倍和2.00倍.结论:MTHFR基因C677T突变基因型与乳腺癌的易感性有关.     

亚甲基四氢叶酸还原酶基因多态性与肝癌关系探讨

目的探讨亚甲基四氢叶酸还原酶(5,10-methylenetetrahydrofolate reductase,MTHFR)基因多态性与中国人群原发性肝癌危险度的关系,及与危险因素结合对危险度影响.方法以人群为基础的病例对照研究,包括204例确诊的新发原发性肝癌病例以及415例健康对照.MTHFR C677T和A1298C的基因多态性由PCR-RFLP的方法进行分析.结果MTHFRC/C,C/T,T/T基因型的频率在病例中分别为:25.8%,58.8%,15.5%,在对照中分别为34.5%,50.9%,14.6%.和C/C基因型相比,携带Any T基因型的个体患肝癌的危险度为:1.58(95%CI:1.01-2.48).MTHFR1298各基因型在健康对照中的比例分别为:69.7%(A/A),28.4%(A/C),1.8%(C/C),病例组与对照组频率分布无显著性差异.同时携带MTHFR 677Any T和1298 Any C基因型的个体肝癌危险度上升到2.05(95%CI:0.96～4.36).结合MTHFR677多态性与肝癌的三大主要危险因素(乙型肝炎、饮生水、霉变食物摄入)分析发现所有不同危险因素的暴露组中,携带MTHFR高危基因(Any T基因型)的个体患肝癌危险度均高.同时暴露于3个主要危险因素并携带高危基因型的个体,调整的肝癌危险度上升到71.69.结论MTHFR C677T的基因多态性与肝癌危险度有关,且可以与其他环境危险因素结合影响肝癌的危险度.     

叶酸及亚甲基四氢叶酸还原酶基因多态性与乳腺癌细胞多药耐药的相关性分析

目的:探讨人乳腺癌亲本细胞株(MCF-7)及耐多柔比星乳腺癌细胞株(MCF-7/ADR)中叶酸受体(FOLR)的表达及亚甲基四氢叶酸还原酶(MTHFR)基因多态性与乳腺癌细胞多药耐药的相关性。方法:流式细胞仪检测不同浓度叶酸对MCF-7细胞及MCF-7/ADR细胞周期的影响;RT-PCR检测MCF-7细胞及MCF-7/ADR细胞中FOLR和mdr-1 mRNA的表达水平;PCR-RFLP方法检测MCF-7细胞及MCF-7/ADR细胞中MTHFR基因C677T及A1298C基因多态性。结果:当叶酸≥270nmol/L时,MCF-7和MCF-7/ADR细胞处于G0/G1期细胞数增加。在MCF-7细胞中S期细胞数在叶酸≥270 nmol/L时显著减少(P<0.001);在MCF-7/ADR细胞中S期细胞数在叶酸≥30nmol/L时开始显著减少,且随着叶酸浓度升高,S期细胞数减少更显著(P<0.001)。在两株细胞中,FOLR和mdr-1基因mRNA表达水平呈负相关,MTHFR的C677T基因多态性及A1298C转录水平无差异;但经限制性核酸内切酶反应后,MCF-7细胞的MTHFR基因有A1298C及C677T两种基因多态性;而MCF-7/ADR细胞MTHFR基因只存在C677T基因多态性。结论:叶酸对MCF-7和MCF-7/ADR细胞的DNA合成均有抑制作用,该抑制作用在MCF-7/ADR细胞中更显著,可能通过阻断细胞从G0/G1期进入S期实现。在MCF-7/ADR细胞MTHFR A1298C基因多态性消失,可能与MCF-7细胞耐药相关。     

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。     

5,10-亚甲基四氢叶酸还原酶基因多态性与肺癌的相关性研究

叶酸代谢在肺癌发生过程中占有重要的地位,因为叶酸的代谢同时影响了DNA与核苷酸的合成。5,10-亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR）是一种非常重要的叶酸还原酶,它不可逆地将5,10-亚甲基四氢叶酸催化生成5-甲基四氢叶酸,而后者正是同型半胱氨酸甲基化生成蛋氨酸反应的甲基供体。MTHFR基因的多态性（C677T,A1298C）会造成酶的活性降低,从而影响疾病的发病率。已有研究表明MTHFR的基因多态性与肺癌的发病率显著相关,文章对MTHFR基因多态性与肺癌的关系作一综述。     

亚甲基四氢叶酸还原酶基因多态性与非小细胞肺癌化疗敏感性的关系

背景与目的 亚甲基四氢叶酸还原酶（MTHFR）是叶酸代谢的关键酶，在DNA甲基化中起重要作用。体外研究已经证明一些基因的异常甲基化可以影响肿瘤细胞对细胞毒性药物和干扰DNA合成药物的敏感性。本研究旨在观察MTHFR基因C677T、A1298C多态与非小细胞肺癌（NSCLC）患者对铂类药物为基础的化疗方案敏感性的关系。方法 收集经病理学确诊的中、晚期NSCLC病例97例。用PCR—RFLP技术检测患者MTHFR基因型。所有患者均经以铂类为基础的化疗方案治疗。结果 ①97例NSCLC病例中，MTHFRC677TC／C、C／T和T／T基因型频度分别为34．0％、50．5％和15．5％，A1298CA／A、A／C和C／C基因型频度分别为64．6％、29．2％和6．2％。化疗后总有效率（完全缓解＋部分缓解）为39．2％。②分别分析MTHFRC677T多态性和A1298C多态性与化疗疗效的关系时，未发现这两个多态与NSCLC化疗的疗效有明显关系。而联合分析MTHFRC677T多态性A1298C多态基因型与化疗疗效的关系时，发现携带MTHFRC677TT等位基因（C／T或T／T基因型）、同时携带A1298CA／A基因型者的有效率为51．1％，显著高于同时携带C677TC／T基因型及A1298CC等位基因者（12．5％）（P=0．007，OR=7．30，95％CI：1．34～52．47）。结论 MTHFR基因C677T和A1298C多态联合作用可影响NSCLC对化疗的敏感性，MTHFR基因型检测对指导NSCLC的化疗、预测疗效具有较高的临床价值。     

亚甲基四氢叶酸还原酶基因单核苷酸多态性与儿童急性淋巴细胞白血病的相关性

 【摘要】　目的　探讨亚甲基四氢叶酸还原酶基因（MTHFR）单核甘酸多态性与儿童急性淋巴细胞白血病（ALL）发病风险的关系。方法　分别收集45例ALL患儿（ALL组）及45名健康儿童（对照组）外周血各2 ml,提取基因组DNA,应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）法,检测MTHFR C677T和A1298C基因型,比较不同基因型对儿童ALL发病风险的影响。采用Logistic回归模型计算比值比（OR）和95 %可信区间（95 % CI）。结果　对照组MTHFR 677CC、CT和TT基因型基因分布频率分别为31.1 %（14／45）、51.1 %（23／45）和17.7 %（8／45）,ALL组3种基因型分布频率分别为51.1 %（23／45）、40.0 %（18／45）和8.9 %（4／45）,两者比较差异有统计学意义（χ2＝7.48,P＝0.04）;MTHFR 677 T等位基因在ALL组中的检出率为48.8 %（22／45）,在对照组中的检出率为69.9 %（31／45）;T等位基因携带者发生ALL的风险是CC基因型的0.4倍（95 % CI 0.21～0.83）。对照组MTHFR 1298AA、AC和CC基因型基因分布频率分别为57.8 %、40.0 %和2.2 %,ALL组中3种基因型分布频率分别为18.8 %、44.4 %和6.8 %,两者比较差异无统计学意义（χ2＝11.23,P＝0.23）;MTHFR 1298 C等位基因ALL组中的检出率为42.2 %（19／45）,对照组中的检出率为51.1 %（23／45）;C等位基因的存在并不会提高儿童ALL发生的风险（OR＝1.3,95 % CI 0.21～0.83）。结论　MTHFR 677 T等位基因的存在会显著降低儿童发生ALL的风险,而MTHFR 1298各基因型与儿童ALL的发生均无明显相关性。     

Breast cancer risk and methylenetetrahydrofolate reductase polymorphism

Objective. Methylenetetrahydrofolate reductase (MTHFR), a polymorphic enzyme involved in folate metabolism, plays a role in DNA biosynthesis, methylation, and repair in actively dividing cells. Because breast-cell division occurs in women with active ovulatory cycles, polymorphisms in the MTHFR gene could be a risk factor for breast cancer. Methods. We genotyped 352 clinic-based study subjects for MTHFR, 105 subjects with breast cancer and 247 with benign breast disease, histopathologically classified as high-risk or low-risk for breast cancer. Questionnaire data were collected prior to biopsy to blind subjects and interviewers to diagnoses. Results. Premenopausal women with the MTHFR polymorphism had a threefold increased breast cancer risk (OR = 2.8; 95%CI: 1.02–7.51) compared to the clinic-based controls with benign breast disease. Results were similar using either low- or high-risk controls. However, risk for postmenopausal women was not elevated (OR = 0.8; 95%CI 0.4–1.4). No significant interaction between genotype and smoking or alcohol was found, but polymorphic MTHFR decreased the likelihood of drinking alcohol (OR = 0.5; 95%CI 0.3–0.9). Conclusion. These data suggest that polymorphic MTHFR increases risk of premenopausal, but not postmenopausal, breast cancer. These findings should be explored with a larger sample size in order to analyze gene–environment interactions between MTHFR and folate. Once the intricate relationship between diet and breast cancer has been elucidated, new cancer control initiatives can be considered such as folate chemoprevention trials in high-risk individuals.     

ER、PR、HER-2均阴性乳腺癌人群的研究进展

ER、PR和HER-2均为阴性的乳腺癌(三阴乳腺癌)患者是一组特殊的群体,其病理及肿瘤生物学特征有:多为导管癌、组织学分级较高、肿瘤细胞多表达basal细胞角蛋白、EGFR和p53等,并且在表型特征和分子水平上与basal-like乳腺癌和BRCA1相关乳腺癌存在一定的相关性。三阴乳腺癌患者常较早发生局部复发和远处转移,内脏转移率高于骨转移,预后较差,近来研究者开始逐渐重视此亚型群体。由于没有内分泌和靶向HER-2治疗的机会,因此只能将化疗作为主要的治疗手段,目前也有一些关于化疗和靶向治疗等方面的研究报道和临床试验,提示烷化剂、铂类、蒽环类等可能是相对敏感药物,针对EGFR、C-kit和Src等靶点的靶向治疗也有可能发挥较好的治疗效果。但是目前的研究结果还不能明确三阴乳腺癌的生物学特点和最佳治疗策略,本文将有关三阴乳腺癌的最新进展做一综述。     

Mutational analysis of the MTHFR gene in breast cancer patients of Pakistani population

Objectives: Since methylenetetrahydrofolatereductase (MTHFR) maintains the balance of circulating folate and methionine and blocks the formation of homocysteine, its regulation in relation to different cancers has extensively been studied in different populations. However, information on Pakistani breast cancer patients is lacking. The MTHFR gene has two most common mutations that are single nucleotide additions which result in change of amino acids C677T to Ala222val and A1298C to Glu429Ala. Methodology: 110 sporadic breast patients with no prior family history of cancer or any other type of genetic disorders along with 110 normal individuals were screened for mutations in exons 1 to exon 9 using single strand conformational polymorphism, RFLP and sequencing analyzer. Results: The p values for the 677CC, 677CT, and 677TT genotypes were 0.223, 0.006, and 0.077, respectively. Those for the 1298AA, 1298AC, and 1298CC genotypes were 0.555, 0.009, and 0.003, respectively. Conclusions: We found an overall a significant, weak inverse association between breast cancer risk and the 677TT genotype and an inverse association with the 1298C variant. These results for MTHFR polymorphism might be population specific in sporadic breast cancer affected patients but many other factors need to be excluded before making final conclusions including folate intake, population and disease heterogeneity.     

乳腺癌微钙化灶的研究新进展

乳腺微钙化灶是乳腺癌的常见影像学表现之一。通过回顾近期乳腺癌微钙化领域的相关研究,对乳腺癌微钙化灶的成分、形成机制、活检诊断方法、其与临床病理指标间的关系以及新辅助化疗对乳腺癌微钙化灶的影响进行综述,以期发现有待解决的问题和研究的方向。     

三阴乳腺癌的研究进展(英文)

Triple-negative breast cancer (TNBC) is a unique subgroup defined by a lack expression of ER (estrogen receptor), PR(progesterone receptor) and HER2 (human epidermal growth factor receptor 2), which has distinctly biological, clinical and pathological characteristics. This subgroup has close relationship with basal-like and BRCA1 (breast cancer susceptibility gene-1) breast cancers. Since endocrine and HER2-targered therapy can not be applied, chemotherapy is the major mean of therapy. Some studies show tha...     

Associations between 5,10-methylenetetrahydrofolate reductase codon 677 and 1298 genetic polymorphisms and environmental factors with reference to susceptibility to colorectal cancer: a case-control study in an Indian population

Although the incidence rate of colorectal cancer is very low, and rectal cancer remains more common in India, a significant increase in its incidence has been reported for both men and women over the last 2 decades. We evaluated MTHFR genetic susceptibility and common environmental risk factors in the development of colon and rectal cancer, and assessed the interactions between gene and environmental factors with colorectal cancer in a case-control study in the Indian population. The study included 59 colon cancer cases, 243 rectal cancer cases and 291 controls. The variant MTHFR 677T allele is rare, while the 1298C allele is common among Indians. MTHFR 677T showed no association with colon cancer (OR = 0.82; 95% CI 0.28-2.05) and a nonstatistically significantly elevated risk with rectal cancer (OR = 1.51; 95% CI 0.86-2.68), and MTHFR 1298 CC genotype was found to be associated with a significantly decreased risk for both colon cancer (OR = 0.30, 95% CI 0.09-0.81) and rectal cancer (OR = 0.43, 95% CI 0.23-0.80). High intake of nonfried vegetables or fruits was inversely associated with both colon and rectal cancer risk. Especially, the combination of a high intake of nonfried vegetables and MTHFR 1298CC genotype was associated with the lowest rectal cancer risk (OR = 0.22, 95% CI 0.09-0.52). Regarding alcohol consumption, indigenous Indian alcohol drinkers (OR = 2.26, 95% CI 0.86-6.36), and those consuming alcohol for duration more than 20 years (OR = 1.55, 95% CI 0.73-3.33), were at a somewhat higher rectal cancer risk. Moreover, the consumed alcohol amount (gram-years) may be also associated with colon or rectal cancer risk.     

乳腺密度、性激素和乳腺癌关系的研究进展

乳腺密度(mammographic breast density,BD)是乳腺癌危险性独立的预测指标,性激素也在乳腺癌的发展中扮演重要角色,而乳腺密度与性激素的关系仍不明确。本文将对乳腺密度,性激素,乳腺癌的关系进行综述。     

脂肪来源的间充质干细胞与乳腺癌关系研究进展

脂肪来源的间充质干细胞（adipose-derived stem cells,ADSCs）对乳腺癌细胞的影响备受关注。尽管大部分基础实验研究证明ADSCs具有“促肿瘤”的作用,但是临床病例调查分析结果却有所不同。本文系统性回顾了ADSCs的生物学特性,ADSCs在乳腺癌肿瘤微环境中的作用,ADSCs对乳腺癌细胞的影响以及自体脂肪填充或移植的临床现状,对实验室基础研究及临床现状进行综述。