鼠MDM．2SNP309位点与肝细胞癌发病年龄与风险关系的分析

目的：探讨广西地区人群鼠双微粒体-2基因（MDM-2）启动子区309位点单核苷酸多态性（SNP）与肝细胞癌（hepatocellularcarcinoma,HCC）发病年龄和发病风险的关系。方法：运用聚合酶链反应一限制性片段长度多态性方法,对985例HCC病例扣992例非肿瘤对照者的MDM-2SNP309位点（T〉G,rs2279744）基因型进行检测,并分析该SNP与HCC发病年龄和发病风险的关系。结果：经年龄、性别、民族、吸烟、饮酒、HBV及HCV感染等因素校正后,MDM-2SNP309位点与HCC发病风险之间无统计学关联（TGWTT：OR-1．19,95％CI：0．86～1．65;GGwTT：OR-1．28,95％CI：0．89～1．85;TG＋GG＇USTT：OR-1．22,95％CI：0．90～1．66）。在女性HCC患者中,与携带MDM-2sNP309位点TG＋GG基因型的女性HCC患者相比（44．8岁）,携带TT基因型的女性患者HCC发病年龄提前4．6岁（49．4岁）,Logrank检验：x2=7．372,P=0．007。在男性患者中未发现此类似结果。结论：MDM-2SNP309位点多态性可能对HcC的发病风险无单独效应作用,但其TT基因型可能与女性HCC的发病年龄提前有关联。本研究结果需要大样本量的研究进一步验证。     

p53codon72单核苷酸多态性与肝细胞癌发病风险的关系

[目的]探讨广西地区p53基因codon72单核苷酸多态性(SNP)与肝细胞癌(HCC)发病风险的关系。[方法]采用TaqMan MGB探针等位基因分型技术对985例肝癌病例和相匹配的992例非肿瘤对照的p53 codon72(Arg>Pro,rs1042522)基因型进行检测,并分析该SNP与肝癌发病风险的关系。[结果]p53 codon72多态性与肝癌发病风险之间无统计学关联(Arg/Pro:校正OR=1.15,95%CI:0.83～1.59;Pro/Pro:校正OR=1.16,95%CI:0.80～1.68;Arg/Pro+Pro/Pro:校正OR=1.15,95%CI:0.85～1.57)。按是否吸烟、饮酒、HBV和HCV感染分层分析,亦未发现p53 codon72多态性与肝癌发病风险有关。但基因—环境交互作用显示,该基因多态性与吸烟、饮酒和HBV感染存在交互作用,OR值分别为2.42(95%CI:1.47～3.97)、2.96(95%CI:1.82～4.80)和62.74(95%CI:34.39～114.46)。[结论]p53codon72的单独效应可能与肝癌易感性无关联,但该SNP与吸烟、饮酒和HBV感染存在基因—环境交互作用,增加肝癌的发病风险。     

COX-2基因单核苷酸多态性与肝细胞癌关联的研究

目的:探讨广西地区COX-2基因-1195G>A(rs689466)和8473T>C(rs5275)位点单核苷酸多态性与肝细胞癌(HCC)遗传易感性的关系。方法:采用以医院为基础的病例对照研究方法。研究对象为780例经组织学确诊的HCC患者和780例相同地区、年龄、性别和民族频数匹配的非肿瘤患者。运用Taq Man MGB探针等位基因分型技术进行COX-2基因单核苷酸多态性的检测,以χ2检验和非条件Logistic回归模型分析比较病例和对照两组间各位点基因型频率分布的差异及其与HCC患病风险的关系,并进一步探讨基因-环境的交互作用对HCC患病风险的影响。结果:COX-2基因单位点-1195G>A或8473T>C多态与HCC患病风险无统计学相关性(显性模型下SNP-1195G>A:校正OR=1.32,95%CI:0.94~1.85;SNP8473T>C:校正OR=0.87,95%CI:0.64~1.18)。分层分析显示,显性模型下COX-2基因-1195G>A位点GA+AA基因型增加年龄<55岁者患HCC的风险(校正OR=1.56,95%CI:1.03~2.37),而8473T>C位点TC+CC基因型可降低女性患HCC的风险(校正OR=0.50,95%CI:0.25~0.99)。进一步交互作用分析显示,COX-2基因-1195G>A位点与年龄、8473T>C位点与性别分别存在交互作用(P=0.002;P=0.007)。结论:COX-2基因-1195G>A或8473T>C位点SNP的单独效应可能与HCC易感性无关联,但是-1195G>A与年龄、8473T>C位点与性别存在交互作用,影响HCC的患病风险。     

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。      

真核翻译起始因子3遗传变异与HBV相关肝细胞癌发病风险的相关性

目的 探讨真核翻译起始因子3(eukaryotic translation initiation factor 3,eIF3)遗传变异与乙型肝炎病毒相关肝细胞癌（HBV-HCC）发病风险的关系。方法 本研究采用两阶段病例对照研究的方法,发现阶段以广西的966例HCC病例和1 003例乙型肝炎病毒表面抗原（hepatitis B surface antigen,HBsAg）阳性对照为研究对象,筛选出与HCC发病风险有关联的单核苷酸多态性（single nucleotide polymorphisms,SNP）位点,验证阶段采用上海的480例HCC病例和484例HBsAg阳性对照人群对发现阶段的阳性位点进行验证。通过单因素和多因素logistic回归分析eIF3遗传变异位点与HBV-HCC发病风险的相关性。结果本研究发现EIF3G 3′-UTR区2个具有潜在功能的SNPs(rs7401 A>G和rs23057952 A>G)与HBV-HCC的发病风险相关。其中与A等位基因携带者相比,rs7401 G等位基因携带者的HBV-HCC发病风险增加（OR=1.18,95%CI:1.02...     

红细胞补体受体1单核苷酸多态性与肝细胞癌发病风险的研究

目的 探讨红细胞补体受体1（CR1）单核苷酸多态性（SNP）与肝细胞癌（HCC）发病的关系。方法 收集102例HCC患者（HCC组）和98例健康体检者（对照组）的外周血样本,选取CR1的5个标签SNP位点（rs4844600 G＞A、rs17048010 T＞C、rs3818361 C＞T、rs11118167 T＞C和rs9429945 C＞T）进行检测,分析两组的红细胞CR1基因各SNP位点基因型、等位基因及单体型的分布差异及其与HCC患病风险的关系。同时按照性别、年龄相匹配的原则分别从对照组和HCC组中选取52例和53例样本采用流式细胞术检测其红细胞CR1的几何平均荧光强度比值（GMFIR）。结果 两组rs4844600 G＞A基因型和等位基因分布的差异有统计学意义（P＜0.01）。CR1基因rs4844600 G＞A／GG基因型携带者患HCC的风险为非携带者的2.458倍（95％ CI：1.357～4.451）,GA基因型携带者患病风险是非携带者的0.404倍（95％CI：0.218～0.746）,其等位基因G携带者患病风险为非携带者的1.945倍（95％CI：1.183～3.199）。rs17048010 T＞C、rs3818361 C＞T、rs11118167 T＞C、rs9429945 C＞T这4个SNP位点和rs11118167-rs3818361-rs17048010／TCT、TTC、CCT、TTT这4种单体型与HCC的患病风险无关（P＞0.05）。HCC组CR1的GMFIR水平为3.257±1.191,高于HCC组的2.652±0.789,差异有统计学意义（t=2.644,P=0.008）。结论 HCC患者红细胞免疫功能降低,CR1基因SNP位点rs4844600 G＞A与HCC发病关联。     

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。     

肝细胞癌组织中MMP-2的表达与侵袭转移的关系

目的:探讨人肝细胞性肝癌(hepatocellularcarcinoma,HCC)中基质金属蛋白酶2(matrixmetalloproteinase2,MMP2)的表达与其侵袭转移的关系。方法:用半定量逆转录PCR(RTPCR)方法检测癌、癌旁组织及正常组织中MMP2mRNA的表达;用免疫组织化学方法检测癌、癌旁组织及正常组织中MMP2蛋白质的表达。结果:MMP2在肝癌中的表达高于癌旁组织和正常组织,差异有统计学意义,P<0.05;癌旁组织和正常组织中MMP2的表达差异无统计学意义,P>0.05。癌组织中MMP2的表达与术后复发时间呈负相关,P=0.013,R2=0.842;与病理学分级呈正相关,P=0.000,R2=0.797。癌组织中MMP2的表达与肝外转移呈正相关,P=0.003,R2=0.834。癌旁组织中MMP2的表达与术后复发时间呈负相关,P=0.021,R2=0.877。结论:MMP2与肿瘤的分化程度、侵袭、转移能力和复发倾向相关。在临床中可望作为肿瘤分化、复发和转移的评估指标之一。     

肝细胞癌骨转移的分子预测模型

肝细胞癌( hepatocellular carcinoma,HCC)在全球男性患者中发病率居第5位,女性中居第8位[1],居世界癌症死亡率的第3位.每年全世界新发56万HCC患者,约占年新发癌症患者的6％[2].骨转移是影响HCC患者生存期和生活质量的重要因素.HCC骨转移患者预后很差,中位生存期仅5.0 -7.4月.HCC骨转移患者常出现剧烈骨痛、病理性骨折、神经功能障碍甚至瘫痪,严重影响患者生活质量和生存期.随着HCC诊疗水平的提高,HCC骨转移发生率逐年上升,骨转移占HCC肝外转移的38.5％[3].     

MDM2 SNP309T>G polymorphism and hepatocellular carcinoma risk: a meta-analysis

Case–control studies on the association between mouse double-minute 2 homolog (MDM2) SNP309T>G polymorphism and hepatocellular carcinoma have provided either controversial or inconclusive results. To clarify the effect of MDM2 SNP309T>G polymorphism on the risk of hepatocellular carcinoma, a meta-analysis of all case–control observational studies was performed. Pooled odds ratios (ORs) for various polymorphisms were estimated using random and fixed effects models. The Q-statistic was used to evaluate the homogeneity, and Egger and Begg tests were used to assess publication bias. Overall, the MDM2 SNP309T>G polymorphism was associated with a risk of hepatocellular carcinoma (OR?=?0.68; 95 % CI?=?0.54–0.85 for allele contrast, p?=?0.0005, p _het?=?0.004). The contrast of homozygotes and the recessive and dominant models produced the same pattern of results as the allele contrast. In the analysis stratified by ethnicity, significant associations were found in the Caucasian population in all of the genetic models. In addition, heterogeneity disappeared in subgroups of Caucasian subjects. Our pooled data suggest evidence for a major role of MDM2 SNP309T>G polymorphism in the carcinogenesis of hepatocellular carcinoma, especially among Caucasian populations.     

Role of the MDM2 SNP309 polymorphism in the initiation and early age of onset of nasopharyngeal carcinoma

Recent studies refer that amplification/overexpression of the principal negative regulator of p53 (Mdm2) is frequently found in several malignancies. Several studies have associated a polymorphism (SNP309 T/G) in the promoter region of MDM2 with higher levels of this protein, which will favor p53‐pathway abolishment, cell‐cycle escape, and development of cancer. We aimed to study if MDM2 SNP309 T/G polymorphism contributes to the development of nasopharyngeal carcinoma (NPC). We have developed a case–control study with 124 patients with NPC and 509 healthy individuals from the north of Portugal to determine the genetic distribution of the MDM2 SNP309 polymorphism in DNA extracted from peripheral blood samples. Statistical analysis was performed to compare categorical variables adjusted for age and gender by multivariate logistic regression. Genotype‐specific distributions according to age of onset were tested by Kaplan–Meier method and analyzed by Cox‐regression proportional hazard model adjusted for gender. This study revealed that MDM2 SNP309 GG homozygous represent an increased risk adjusted for age and gender to develop NPC (OR = 2.15), with particular effect in undifferentiated types (OR = 2.46) and early clinical stages (OR = 3.32). We also found that median age of onset of NPC was significantly different (55.2 vs. 61.6) with increased effect in undifferentiated types (55.2 vs. 61.9) and early clinical stages (55.3 vs. 65.3). Our study suggests that MDM2 SNP309 can be considered a risk marker for the development of NPC mainly in early ages probably as an initiation marker for potential cancer development. © 2010 Wiley‐Liss, Inc.     

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.     

MDM2 SNP309 does not confer an increased risk to oral squamous cell carcinoma but may modulate the age of disease onset

The MDM2 SNP309 has been associated with increased expression of the protein which could suppress p53 function, and has been shown to modulate risk to cancer. We have previously shown that overexpression of MDM2 is a common event in oral cancers. In the present study, we determined the association between the MDM2 SNP309 polymorphism and oral cancer in 207 oral cancer patients and 116 normal subjects. We genotyped the MDM2 SNP309 by PCR-RFLP. Logistic regression was adapted to calculate odds ratios for MDM2 SNP309 polymorphism from univariate and multivariable adjusted models. Our results suggest that MDM2 SNP309 does not confer increased risk to oral cancer (OR=1.55, 95% CI=0.77-3.11). However, the GG/TG genotype was associated with later disease onset in women above 55 years of age. Collectively, our data suggests that MDM2 SNP309 may modulate the risk to oral cancer and is a modifier of the age at oral cancer onset in women above the age of 55 years.     

MDM2 SNP309T>G polymorphism and risk of hepatocellular carcinoma: A case–control analysis in a Moroccan population

Background: The Murine double minute 2 (MDM2) gene encodes a negative regulator of the p53 tumor suppressor protein. A single nucleotide polymorphism (SNP) in the MDM2 promoter (a T to G exchange at nucleotide 309) has been reported to produce accelerated tumor formation. The aim of this study was to investigate whether this functional SNP is associated with an enhanced risk of liver tumorigenesis in Moroccan patients. Methods: The study consisted in the comparison of 96 hepatocellular carcinomas (HCC) cases and 222 controls without HCC matched for age, gender and ethnicity. PCR–RFLP and sequencing methods were used to determine the genotype at the MDM2 SNP309T>G locus. Results: Overall, our results indicate that the GG genotype of SNP309 is significantly associated with an increased risk of HCC (odds ratio, OR = 2.60, 95% CI, 1.08–6.28). Interestingly, despite a wide range of confidence interval, there is a trend associating the GG genotype with a high risk of HCC in males (OR = 3.31; 95% CI, 0.93–11.82) and in HCV-infected patients (OR = 3.7; 95% CI, 0.82–16.45). By contrast, no association between age at diagnosis and MDM2 SNP309 genotypes was observed in HCC patients (P = 0.610). Conclusion: Our findings suggest that the MDM2 309T>G polymorphism is an important modulator of hepatocellular carcinoma development in Moroccan patients.