MDM2基因SNP309多态性与宫颈癌的相关性研究

目的：研究汉族妇女中MDM2基因SNP309多态性与宫颈癌易感性及临床病理学参数之间的关系。方法：用DNA抽提试剂盒从研究对象的外周血标本中抽提基因组DNA, 其中宫颈癌患者105例, 正常对照组140例; 用聚合酶链式反应-限制性片段长度多态 （PCR-RFLP） 和直接测序方法测定MDM2-SNP309单核苷酸多态基因型。结果：宫颈癌患者的MDM-SNP309 G等位基因频率显著高于对照组 （60.0% vs 48.6%, P=0.012; OR=1.59, 95% CI=1.11～2.28）; 宫颈癌与对照组之间的GG、 TG和TT等位基因型的分布差异有统计学意义, 其中GG等位基因型在宫颈细胞癌中的频率显著高于对照组 （36.2% vs 18.6%, P=0.016; OR=2.58,95% CI=1.19～5.61）。在宫颈癌组中, 淋巴转移阳性组MDM2-SNP309 GG等位基因型显著高于淋巴转移阴性组 （31.8% vs 11.5%, P<0.05）, SNP309单核苷酸多态性分布与肿瘤组织学类型、病理分级及肿瘤大小无关。结论:MDM2基因SNP309 GG基因型是宫颈癌发生的遗传易感因素, 与宫颈癌的淋巴转移发生有相关性。     

MDM2 启动子区309 位点基因多态性与乳腺癌风险的关系*

目的:采用病例- 对照研究检测MDM2 启动子区309 位点T>G 单核苷酸多态（SNP 309）在中国女性人群中的频率分布,分析其与中国女性乳腺癌发病风险的关系。方法:提取病例组698 例原发性乳腺癌患者及对照组525 例健康人的外周血单核细胞DNA,采用聚合酶链反应- 限制性片段长度多态性（PCR-RFLP ）分析法,检测MDM2 启动子区309 位点基因多态性,确定此位点三种基因型,即T/T、T/G、G/G 基因型。统计分析病例组和对照组人群MDM2 SNP 309 各基因型频率分布,及各基因型与乳腺癌发病风险的相关性。结果:在研究的病例组与对照组整体人群中,经年龄、月经状态、家族史及生育史等因素校正后,与MDM2 SNP 309 T/T基因型比较,T/G 型及G/G 型与乳腺癌的发病风险无显著相关性（T/G,adjusted OR= 1.2,95%CI:0.8～1.6,P=0.30;G/G,adjusted OR= 1.0,95%CI:0.7～1.5,P=0.88）。 进一步分层分析后显示:在绝经后人群中,与T/T基因型比较,T/G 基因型及G/G 基因型显著增加乳腺癌的发病风险（T/G,adjusted OR= 1.8,95%CI:1.2～3.0,P=0.011;G/G,adjusted OR= 1.9,95%CI:1.2～3.3,P=0.014）。 提示绝经后人群携带T/G 型、G/G 型者比携带T/T基因型者患乳腺癌的风险分别升高约1.8、1.9 倍。在绝经前人群中,各基因型与乳腺癌的发病风险无显著相关性（P>0.05）。 结论:MDM2 启动子309 位点突变型G 等位基因携带者显著增加绝经后女性乳腺癌的发病风险。      

MDM2启动子309位点多态性与乳腺癌易感性关系的Meta分析

[目的]综合评价MDM2（routine double minute2）基因启动子309位点多态性与乳腺癌易感性的关系。[方法]检索中国医学文献数据库和PubMed中MDM2基因SNP309与乳腺癌易感性关系的病例对照研究,并用Meta分析的方法合并SNP309与乳腺癌易感性OR值。然后进行其中有家族史的乳腺癌亚组分析,敏感性分析和文献的发表偏倚检验。[结果]Meta分析共纳入10篇文献,乳腺癌家族史组有3篇;累计病例7535例,对照8272例,G等位基因相对于T等位基因0R值为1．01（95％CI：0．96～1．06）。乳腺癌家族史组G等位基因相对于T等位基因OR值为1．06（95％CI：0．94～1．19）。[结论]MDM2基因309T〉G多态与乳腺癌易感性无统计学意义。     

MDM2基因SNP309可能与早发性乳腺癌易感性无关:福建病例-对照研究

背景与目的:MDM2基因是p53基因的负性调控因子,其SNP309遗传多态性可能与乳腺癌发病风险有关,本研究探讨SNP309多态性在福建早发性乳腺癌人群中的分布及其与乳腺癌发病风险的相关性.方法:对123例早发性乳腺癌患者(发病年龄≤35岁)和101例正常对照者进行MDM2基因SNP309(T>G,rs2279744)的PCR扩增,并采用时间飞行质谱分析(MALDI-TOF-MS)法鉴定多态性的基因型,比较基因型分布和发病风险的关系;危险度OR及95%CI应用非条件Logistic回归分析计算.结果:MDM2基因SNP309多态性基因型在正常对照组和病例组中的分布频率分别为TT:28(27.7%)/26(21.1%),TG:50(49.5%)/61(49.6%),GG:23(22.8%)/36(29.3%);两组间分布频率差异无统计学意义(P>0.05).Logistic回归分析表明,在早发性乳腺癌人群中,以rs2279744的TT基因型为参照,含G基因型(TG,GG)未显著性地提高乳腺癌的发病危险,OR=1.358(95%CI:0.706～2.614,P>0.05).结论:MDM2基因SNP309(T>G,rs2279744)多态性可能与福建地区汉族人群早发性乳腺癌的遗传易感性无关,其作为低外显率的乳腺癌易感基因位点尚不明确,作为未来临床基因筛查的候选指标还需谨慎.     

MDM2基因多态性与NSCLC辐射敏感性及易感性的相关性

研究表明鼠双微体2（murine double minute 2,MDM2）基因的扩增和（或）过度表达可见于多种肿瘤，如淋巴瘤，乳腺癌和睾丸精子细胞肿瘤，MDM2在肺癌中的表达是一个常见现象。因此，MDM2在非小细胞肺癌（NSCLC）易感性及辐射敏感性中的作用是值得肿瘤学家们探讨的问题，笔者采用PCR-RFLP方法检测80例NSCLC及82例正常人MDM2基因单核苷酸多态性（SNP），旨在探讨MDM2基因多态性与NSCLC易感性及辐射敏感性是否存在相关性。     

MDM2启动子309位点多态性与肺癌易感性关系的Meta分析

目的:综合评价MDM2 (murine double minute 2)基因启动子309位点多态性与肺癌易感性的关系.方法:检索中国医学文献数据库和PubMed,以得到MDM2基因SNP309与肺癌易感性关系的病例对照研究,并用Meta分析的方法合并SNP309与肺癌易感性关系的OR值.然后进行亚组分析、敏感性分析和文献的发表偏倚检验.结果:本次Meta分析共纳入6篇文献,累计病例4276例,对照5318例,G等住基因相对于T等位基因OR值为1.11(95%CI为0.97～1.26,P=0.14),差异无统计学意义,但在未吸烟亚组中OR值为1.32(95%CI为1.15～1.52,P=0.000),差异有统计学意义.结论:MDM2基因309T>G多态与肺癌易感性的关系差异无统计学意义,但在未吸烟亚组中SNP309G等位基因是一个肺癌危险因子.     

MDM2基因rs2279744多态性与肝细胞癌关联性分析

目的:探讨MDM2基因rs2279744多态性与肝细胞癌(HCC)的发病及预后的关系。方法:采用以医院为基础的病例-对照研究方式通过TaqMan-PCR检测分析192例HCC患者和192名健康志原者的MDM2基因rs2279744的基因型,通过Logistic回归、Kaplan-Meier法和Cox比例风险回归模型等分析该多态性与HCC发病及预后的关系。结果:带有MDM2rs2279744G等位基因的基因型(MDM2-TG和-GG)在HCC组的频率要高于对照组(P=1.77×10-9),与不带有G等位基因者(MDM2-TT)相比,其所致HCC发病风险分别为2.86(1.68～4.85)和4.84(2.90～8.09);该多态性增加肿瘤血道转移风险(OR=1.75);生存分析显示,MDM2-TG和-GG影响HCC术后无病生存及总体生存(P<0.01)。结论:MDM2基因rs2279744多态性影响HCC发病及预后。     

MDM2基因多态性与肝细胞肝癌易感性的关系研究

目的:探讨小鼠双微体基因(murine double minute 2,MDM2)单核苷酸多态性(SNP)与肝细胞肝癌易感性及生物学行为的关系。方法:对166例肝癌病例和157例健康对照病例的外周血标本,利用SYBRGREEN PCR溶解曲线法分析MDM2基因型。结果:实验组等位基因的发生率(T,0.49;G,0.51)与对照组基因的发生率(T,0.59;G,0.41)(P=0.015)有统计学差异。肝癌患者中GG基因型的发生率(22.29%)高于健康人群(13.38%)(P=0.010)。结论:与TT基因型相比,携带G等位基因或GG型与肝癌发生的相关性较大。     

ADIPOQ基因多态性与前列腺癌易感性的相关性研究

背景与目的：环境因素在前列腺癌发病机制中的作用,尤其是高脂肪摄入饮食、缺乏体力活动等引起的肥胖逐渐受到重视。脂联素可能是前列腺癌与肥胖之间潜在的分子递质,本研究旨在探讨编码脂联素的ADIPOQ基因多态性与中国人群前列腺癌发病风险的关联性。方法：提取917例前列腺癌患者和1 036例正常对照男性的外周血DNA,通过TaqMan探针技术检测ADIPOQ基因rs266729和rs182052的多态性。采用Logistic回归模型分析各基因型与前列腺癌发病风险的关系,在此基础上分析其与体质量指数的关系。结果：对照组中rs266729和rs182052两位点的基因型频率均符合Hardy-Weinberg平衡（P=0.29和0.83）。rs266729和rs182052两位点各基因型在两组间的分布差异无统计学意义（P=0.88和0.63）。与野生型相比,两位点的杂合型及突变型携带者患病风险差异无统计学意义（OR=0.97,95%CI：0.81~1.16;OR=0.89,95%CI：0.73~1.09）。分层分析显示,在年龄≤69岁的人群中,rs182052 AA基因型携带者的前列腺癌发病风险仅为AG或GG基因型携带者的73%（95%CI：0.54~0.99）,差异有统计学意义（P=0.04）。rs182052遗传变异与体质量指数相关（P=0.03）。结论：ADIPOQ基因rs266729和rs182052可能与中国人群前列腺癌总体发病风险无关,rs182052 AA基因型携带者≤69岁时发病风险较低,并且该位点的遗传变异与前列腺癌患者的体质量指数相关。     

FGFR2基因多态性与乳腺癌的相关性研究

目的:探讨成纤维细胞生长因子受体2基因(FGFR2)第二内含子单核苷酸多态性在女性群体中的频率分布及其与女性乳腺癌易感性之间的相关性.方法:运用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法结合琼脂糖凝胶电泳技术,对106例女性乳腺癌患者(乳腺癌组)和116例正常女性(对照组)对照进行检测,分析两组贵州地区人群FGFR2基因第二内含子的两个单核苷酸多态性位点rs2420946和rs2981579的基因及基因型的分布情况.结果:乳腺癌组FGFR2基因单核苷酸多态性位点rs2420946的基因型(AA,AG.CG)频率分别为15.09%、48.11%、36.79%,对照组为18.10%、43.97%、37.93%;乳腺癌组与对照组A等位基因频率分别为39.15%和40.09%,G等位基因频率分别为60.85%和59.91%;两组人群分别进行比较,基因型及等位基因频率分布的差异均无统计学意义(P>0.05);FGFR2基因rs2981579的基因型(CC,CT,TT)频率在乳腺癌组分别为30.19%、45.28%、24.53%,对照组为27.59%、48.28%、24.14%;乳腺癌组与对照组c等位基因频率分别为52.83%和51.72%,T等位基因频率分别为47.17%和48.28%;两组人群分别进行比较,基因型频率与等位基因频率分布的差异均无统计学意义(P>0.05).结论:FGFR2基因第二内含子的两个单核苷酸多态性位点rs2420946及rs2981579在乳腺癌及对照人群中基因型频率与等位基因频率分布差异均无统计学意义,提示两个位点的多态性与乳腺癌无明显相关性.     

Association between MDM2 promoter SNP309 T/G polymorphism and liver cancer risk - a meta-analysis

Background: Many studies have investigated the association between the MDM2 promoter SNP309 T/Gpolymorphism and liver cancer risk, but inconsistencies make drawwing definitive conclusions difficult. Methods:We therefore searched main databases for articles relating MDM2 SNP309 T/G polymorphism to risk of livercancer in humans and estimated summary odds ratio (OR) with 95% confidence intervals (95% CI) to assessthe possible association in a meta-analysis. Results: The main analysis revealed no significant heterogeneity, andthe pooled ORs of fixed-effects were all significant (for G versus T, OR = 1.59, 95% CI 1.42-1.78; for GG versusTT, OR = 2.45, 95% CI 1.93-3.12; for GT versus TT, OR = 1.70, 95% CI 1.38-2.09; for GG versus GT, OR =1.49, 95% CI 1.24-1.79; for GG and GT versus TT, OR = 1.95, 95% CI 1.61-2.38; for GG versus TT and GT,OR = 1.73, 95% CI 1.46-2.07). Subgroup analyses by ethnicity and sensitivity analyses both showed associationsto remain significant. Conclusion: The present meta-analysis of available data showed a significant associationbetween the MDM2 SNP309 T/G polymorphism and liver cancer risk, the MDM2 SNP309 G allele contributingto increased risk in both Asians and Caucasians in a graded, dose-dependent fashion.     

No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer

A functional T to G germline polymorphism in the promoter region of MDM2 (SNP309) has been reported to profoundly accelerate tumor formation suggesting that it may also represent a powerful cancer predisposing allele. To investigate the role of SNP309 in cancer predisposition we undertook a case-control study of this polymorphism among 351 women diagnosed with breast cancer, 302 women diagnosed with ovarian and 258 female controls from a British population. The GG genotype was not associated with either breast cancer (OR 1.04, 95% CI 0.67–1.60) or ovarian cancer (OR 0.86, 95% CI 0.53–1.37). This study has found no evidence that the GG genotype of the MDM2 SNP309 polymorphism is associated with early onset or familial breast cancer or with ovarian cancer.     

Meta-analysis of Associations between the MDM2-T309G Polymorphism and Prostate Cancer Risk

The mouse double minute 2 (MDM2) gene plays a key role in the p53 pathway, and the SNP 309T/G singlenucleotidepolymorphism in the promoter region of MDM2 has been shown to be associated with increased riskof cancer. However, no consistent results were found concerning the relationships between the polymorphismand prostate cancer risk. This meta-analysis, covering 4 independent case-control studies, was conducted tobetter understand the association between MDM2-SNP T309G and prostate cancer risk focusing on overall andsubgroup aspects. The analysis revealed, no matter what kind of genetic model was used, no significant associationbetween MDM2-SNP T309G and prostate cancer risk in overall analysis (GT/TT: OR = 0.84, 95%CI = 0.60-1.19;GG/TT: OR = 0.69, 95%CI = 0.43-1.11; dominant model: OR = 0.81, 95%CI= 0.58-1.13; recessive model: OR =1.23, 95%CI = 0.95-1.59). In subgroup analysis, the polymorphism seemed more likely to be a protective factorin Europeans (GG/TT: OR = 0.52, 95%CI = 0.31-0.87; recessive model: OR = 0.58, 95%CI = 0.36-0.95) thanin Asian populations, and a protective effect of the polymorphism was also seen in hospital-based studies in allmodels (GT/TT: OR = 0.74, 95%CI = 0.57-0.97; GG/TT: OR = 0.55, 95%CI = 0.38-0.79; dominant model: OR= 0.69, 95%CI = 0.54-0.89; recessive model: OR = 0.70, 95%CI = 0.51-0.97). However, more primary studieswith a larger number of samples are required to confirm our findings.     

Meta-analysis of the MDM2 T309G Polymorphism and Gastric Cancer Risk

Background: Mdm2 binds to the amino-terminus of p53 to induce its degradation and a single nucleotidepolymorphism in the MDM2 promoter region (T309G) has been reported to increase the risk of several carcinomas,such as gastric cancer. However, the results of published studies to analyze the association between MDM2 T309Gand gastric cancer havve often conflicted. Methods: To better illustrate the filiation between MDM2 T309G andgastric cancer, we performed a meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were usedto evaluate the strength of the relationship. The pooled ORs were performed for 4 models, additive, recessive,co-dominant model, and dominant. Results: Nine published case-control studies including 3,225 gastric cancercases and 4,118 controls were identified. The MDM2 T309G polymorphism was associated with a significantlyincreased risk of gastric cancer risk when all studies were pooled into the meta-analysis (GG versus TT, OR=1.57;95%CI=1.57-2.12; p=0.003) and GG versus GT/TT, OR=1.52; 95%CI=1.217-1.90; p<0.001). Furthermore, Egger’stest did not show any evidence of publication bias (P = 0.608 for GG versus TT). Conclusion: Our results suggestthat the MDM2 T309G polymorphism is indeed associated with a significantly increased risk of gastric cancer.     

荧光定量ＰＣＲ法检测ＭＤＭ２Ｔ３０９Ｇ位点多态性

目的　建立一种简便易行的ＭＤＭ２基因单核苷酸多态性（ＳＮＰ）３０９位点的检测方法。方法　用ＤＮＡ提取试剂盒提取外周血ＤＮＡ,建立ＭＤＭ２ＳＮＰ３０９位点荧光定量ＰＣＲ熔解曲线检测法。应用煮沸法处理血样取得粗制ＤＮＡ,行荧光定量ＰＣＲ检测,建立位点特异引物法检测ＭＤＭ２ＳＮＰ３０９位点基因型。比较静置不同时间、反复冻融等处理以及存在血液学指标异常的血样经煮沸法提取ＤＮＡ对荧光定量ＰＣＲ扩增反应的影响,通过观察ＰＣＲ扩增情况,评估不同处理方法对ＰＣＲ扩增反应的影响。结果　荧光定量建立ＭＤＭ２ＳＮＰ３０９位点ＰＣＲ检测方法。煮沸法提取的ＤＮＡ可用于普通ＰＣＲ、荧光定量ＰＣＲ扩增体系,且煮沸法处理血样具有较广的适用范围。结论　采用ＭＤＭ２基因ＳＮＰ３０９位点特异性引物行荧光定量ＰＣＲ检测法是一种简便易行的ＭＤＭ２基因ＳＮＰ３０９位点检测方法,该方法有较好的临床适用性。     

MDM2 SNP309 polymorphism contributes to endometrial cancer susceptibility: evidence from a meta-analysis

Objective

The SNP309 polymorphism (T-G) in the promoter of MDM2 gene has been reported to be associated with enhanced MDM2 expression and tumor development. Studies investigating the association between MDM2 SNP309 polymorphism and endometrial cancer risk reported conflicting results. We performed a meta-analysis of all available studies to explore this association.

Methods

All studies published up to August 2013 on the association between MDM2 SNP309 polymorphism and endometrial cancer risk were identified by searching electronic databases PubMed, Web of Science, EMBASE, and Chinese Biomedical Literature database (CBM). The association between the MDM2 SNP309 polymorphism and endometrial cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).

Results

Eight case–control studies with 2069 endometrial cancer cases and 4546 controls were identified. Overall, significant increase of endometrial cancer risk was found when all studies were pooled in the meta-analysis (GG vs. TT: OR = 1.464, 95% CI 1.246–1.721, P < 0.001; GG vs. TG + TT: OR = 1.726, 95% CI 1.251–2.380, P = 0.001; GG + TG vs. TT: OR = 1.169, 95% CI 1.048–1.304, P = 0.005). In subgroup analysis by ethnicity and HWE in controls, significant increase of endometrial cancer risks were observed in Caucasians and studies consistent with HWE. In subgroup analysis according to study quality, significant associations were observed in both high quality studies and low quality studies.

Conclusions

This meta-analysis suggests that MDM2 SNP309 polymorphism contributes to endometrial cancer susceptibility, especially in Caucasian populations. Further large and well-designed studies are needed to confirm this association.     

The association between the T309G polymorphism of the MDM2 gene and sensitivity to anticancer drug is dependent on the p53 mutational status in cellular models

Background:

We investigated, in the panel of 60 human tumour cell lines of the National Cancer Institute (NCI-60), whether the R72P polymorphism of TP53 and the T309G polymorphism of MDM2 were associated to the in vitro cytotoxicity of anticancer agents, extracted from the NCI database. For validation, the same study was performed independently on a second panel of tumour cell lines, JFCR-45.

Methods:

Both SNPs were identified in cell DNA using PCR-RFLP techniques confirmed by direct sequencing and by pyrosequencing. For the analysis of the results, the mutational status of p53 was taken into account.

Results:

In the NCI-60 panel, the TP53 rare-allele frequency was 32% and the MDM2 rare-allele frequency 39%. The MDM2 alleles were distributed according to Hardy–Weinberg equilibrium whereas this was only found, for the TP53 alleles, in p53 non-mutated cell lines. Comparable results were obtained in the JFCR-45 validation set. The TP53 SNP had low impact on anticancer drug cytotoxicity in either panel. In contrast, the MDM2 gene polymorphism had a major impact on anticancer drug cytotoxicity, essentially in p53 non-mutated cell lines. Presence of the rare allele was associated to significantly higher MDM2 protein expression and to increased sensitivity to DNA-interfering drugs. In the JFCR-45 panel, a similar effect of the MDM2 gene polymorphism was observed, but was less dependent on the p53 mutational status.

Conclusions:

We hypothesised that cell lines harbouring the MDM2 G allele presented a lower availability of p53 for DNA repair, translating into higher sensitivity to DNA-damaging agents.