microRNA结合位点单核苷酸多态性与肿瘤易感性的研究进展

恶性肿瘤已成为人类第一死因,严重威胁人类的生存与健康,微小核糖核酸(miRNA)是一类内源性单链非编码小RNA,在转录后水平对靶mRNA的表达进行调控.miRNA结合位点单核苷酸多态性(SNP)使miRNA与靶mRNA原有的结合过程发生异常,使miRNA原有调控网络异常,从而参与肿瘤的发生发展.本文结合最新研究进展,就miRNA结合位点SNP与肿瘤的易感性作一简要综述,旨在为恶性肿瘤的一级预防和早期诊断提供参考.     

凋亡基因Caspase3和Caspase7单核苷酸多态性与胃癌遗传易感性研究

目的 Caspase家族的SNP在乳腺癌、头颈部肿瘤、食管癌、肺癌等癌症中研究较多,而Caspase3,7的SNP与中国人群胃癌发病风险之间的研究较少。本实验旨在利用大样本研究Caspase3和Caspase7基因的SNP与胃癌遗传易感性的关系。方法 收集东北地区胃癌病例1 000例、对照组1 036例血液标本,进行基因组DNA提取。根据NCBI的dbSNP数据库和HapMap数据库,对Caspase 3,7选择潜在的SNP位点,所选位点均位于Caspase3,Caspase7的3′UTR。对Caspase 3,7的SNP位点运用Taqman探针法进行基因型分型。病例对照之间不同变量构成比差异采用双侧χ²检验,对每个位点进行Hardy-Weinberg遗传平衡检验后,采用χ²检验比较病例组和对照组的单个位点基因型频率差异,再通过单因素和多因素Logistic回归模型分析基因型与疾病的关联,对每个位点分层分析比较不同性别、年龄、吸烟、饮酒状况亚层之间基因型与疾病的关联。结果 病例组与对照组的吸烟、饮酒状态以及年吸烟包数(Pack-years)构成存在统计学差异(P＜0.05)。所选位点基因型频率符合Hardy-Weinberg遗传平衡定律(P＞0.05)。将带有风险等位基因的基因型组合后进行分析,显示出针对两个基因来说,带有两个风险基因型的个体比带有0~1个风险基因型的个体患病风险增加了69.6%,调整了协变量影响后带有3个风险基因型的个体比带有0~1个风险基因型的个体患病风险增加了27.6%,带有大于1个风险基因型的个体比带有0~1个风险基因型的个体患病风险增加了35%。两个基因组合之后的分层分析中,年龄≤60岁、男性、从不吸烟、年吸烟包数≤25、胃非贲门腺癌的亚层中风险基因型与疾病有统计学关联,即具有更显著的危险性。结论 本研究所选取的四个位点的SNP均与胃癌风险无关。但通过多因素分析Caspase3、Caspase7的四个位点,带有2个风险基因型比带有0~1个风险基因型的个体患病风险增加。此外,通过分层分析Caspase7的两个位点,其在年龄≤60岁,从不吸烟,年吸烟包数≤25包和非胃贲门腺癌人群中患病风险更为明显。     

Mena表达及SNPs与胃癌遗传易感性及预后

  目的  探讨Mena表达与胃癌侵袭转移的相关性及SNPs与胃癌遗传易感性的关系。  方法  制作模拟胃癌侵袭转移过程的组织芯片,免疫组化染色检测Mena蛋白的表达。PCR-LDR技术检测Mena基因5个SNPs位点多态性并行测序验证。  结果  胃腺癌中Mena表达上调,肠型与混合型胃癌高于弥漫型,并与胃癌侵袭转移负相关,Mena高表达者预后好。Mena基因SNP位点rs3795443的188例对照组等位基因A、G的频率分别为91.0% 和9.0%,胃癌病例组等位基因A、G的频率为82.4% 和17.6%;AA、A/G和GG的基因型频率在对照组分别为81.9%、18.1%和0,而在病例组为68.35%、28.09% 和3.56%,差异具有统计学意义（OR=2.1489,95%CI:1.4607~3.1613,P < 0.01）。5个SNPs位点的基因型和等位基因频率与胃癌术后生存时间均无明显相关性。  结论  胃癌Mena表达升高,组织学类型的维持以及侵袭转移与其表达密切相关,高表达者预后好。Mena SNP rs3795443位点携带等位基因G的GG和A/G基因型个体的胃癌患病风险提高,提示检测该位点基因型有助于评估胃癌的遗传易感性。      

代谢酶基因多态性与胃癌遗传易感性

肿瘤遗传易感性是目前国内外极其关注的研究领域，不同个体对环境致癌物代谢能力的差异决定了个体对肿瘤的易感性。化学致癌物大多为间接致癌物，需经代谢活化后与细胞生物大分子作用而致癌，经解毒酶作用而失活。毒物代谢过程主要包括两类酶：Ⅰ相酶介导氧化代谢，具有活化作用(包括CYP家族)，Ⅱ相酶具有解毒效应(包括GSTs、     

JWA T723G多态性与胃癌易感性

目的探讨JWAT723G多态性与胃癌易感性之间的关系。方法采用多聚酶链反应(polymerase chain reaction,PCR)和变性高效液相色谱法(denaturing high performance liquid chromatography,DHPLC)检测107例胃癌患者和200例同龄健康人群的JWAT723G多态性并进行分析。结果病例组和对照组JWAT723G基因分布频度无显著差异(χ2=2.290,P=0.318)。在调整了性别和年龄后,与T/T基因型相比,T/G基因型发生胃癌的危险性上升到1.21(95%CI:0.94～1.57),G/G基因型发生胃癌的危险性上升到1.49(95%CI:0.45～4.96)。合并T/G和G/G基因型分析显示G等位基因发生胃癌的危险性上升到1.21(95%CI:0.95～1.55),JWAT723G多态性与胃癌的易感性无相关性(P=0.1316)。结论 JWAT723G多态性与胃癌易感性不相关。     

福建地区汉族人群中CLDN23基因SNPs多态性与胃癌遗传易感性及预后的相关性CSCD

目的探讨福建地区汉族人群中已知的三种claudin-23基因CLDN23单核苷酸多态性(SNPs)与胃癌遗传易感性及预后的相关性。方法应用PCR-LDR法检测CLDN23基因3个SNP位点rs12153、rs1060106 和rs11249884的基因型。结果 CLDN23基因SNP位点rs12153、rs1060106及rs11249884三个位点的基因型及等位基因频率在胃癌病例组和健康者之间差异均无统计学意义(P>0.05);胃癌病例组中三个位点的基因型分布频率与肿瘤分化程度、pT分期显著相关(P<0.05);rs12153、rs1060106的基因型分布频率与患者术后生存时间显著相关(P<0.05);CLDN23基因SNP位点rs12153、rs1060106和rs11249884两两之间未见明显的遗传连锁不平衡性;rs12153、rs1060106和rs11249884可能存在的基因单体型中,C-T-G单体型在胃癌病例组与正常对照组之间有显著差异(P<0.01)。结论福建汉族人群中,CLDN23基因SNP位点rs12153、rs1060106及rs11249884的多态性与胃癌的分化、pT分期具有相关性,可能参与胃癌的进展,rs12153、rs1060106的多态性与胃癌患者的预后有关。     

ATM基因单核苷酸多态性与鼻咽癌易感性及复发的相关性

目的:探讨ATM基因单核苷酸多态性与鼻咽癌易感性与复发的关系.方法:采用病例对照研究,采集来自北方地区不同医院的鼻咽癌病人193例、正常人群231例静脉血,酚-氯仿法提取基因,Taqman real-time PCR方法及SDS软件对ATM基因型进行分型.SPSS 13.0软件包进行数据分析,以χ2检验比较SNPs基因型在病例与对照之间分布的差异,以单因素和多因素logistic回归计算比值比(odds ratio,OR)及95%可信区间(confidence interval,CI).结果:单因素分析显示,ATM126713位点的各基因型与鼻咽癌易感性不相关,P值0.075,OR值1.422,95%CI为0.963~2.199.但ATM126713位点的杂合基因型(G/A)经校正年龄、性别、吸烟状态后显示与鼻咽癌易感性相关,P值0.024,OR=1.636,95%CI为1.067~2.509.ATM126713位点各基因型与鼻咽癌复发不相关.结论:ATM126713位点G/A杂合型基因是鼻咽癌风险基因型,ATM126713位点各基因型与鼻咽癌复发无相关性.     

p21WAF1基因多态性与胃癌易感性关系

目的:探讨p21WAF1基因缺失与多态性及其意义。方法:采用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)法和链霉菌抗生物素蛋白-过氧化酶(SP)法分别检测胃癌中p21WAF1基因缺失与多态性和p21蛋白表达。结果:PCR扩增显示,30例胃癌和45例非胃癌标本均无p21WAF1第二外显子缺失。PCR-RFLP发现胃癌和正常胃粘膜p21第二外显子多态性分别为26.7%(8/30)和8.9%(4/45),有显著性差异(P<0.05),且8例具多态性胃癌标本中的正常胃粘膜亦具有这种多态性。p21蛋白阳性表达率,胃癌为43.3%(13/30),非胃癌为100%(45/45),两者有显著性差异(P<0.05),具p21WAF1基因多态性胃癌为37.5%(3/8),与无多态性胃癌45.5%(10/22)无相关性(P>0.05)。结论:胃癌中p21WAF1基因无缺失,而存在多态性。p21WAF1基因多态性和p21表达与胃癌发生有关,但两者无相关性。WAF1     

ZO-1 SNPs与胃癌遗传易感性及预后*

目的：探讨中国福建地区汉族人群中ZO- 1 基因TJP1 4 个已知位点单核苷酸多态性（SNPs）与胃癌遗传易感性及进展和预后的相关性。方法：应用PCR-LDR法检测福建医科大学附属第一医院200 例健康体检个体及220 例原发性胃腺癌患者TJP1基因4 个SNP 位点的基因型。结果：福建地区汉族人群中,TJP-1 SNP rs 7179270 位点稀有等位基因C 的频率为0.2,而其他三个位点（rs 34771010,rs 28578444和rs 41280058）稀有等位基因频率为0.0。TJP1 基因SNP 位点rs 7179270 200 例对照组等位基因C、T 的频率分别为20% 和80% ,胃癌病例组等位基因C、T 的频率为32.6% 和67.4% ;CC、C/T和TT的基因型频率在对照组分别为4% 、32%和64% ,而在病例组为10.9% 、43.2% 和45.9% ,差异具有统计学意义（OR= 1.953,95%CI 1.425～2.677,P<0.001）。 TJP1 rs 7179270位点基因型与胃癌患者的性别、年龄、分化程度、浸润深度、淋巴结转移及手术后生存时间无显著相关（P>0.05）。 结论：TJP1rs 7179270 位点携带等位基因C 的CC和C/T基因型个体的胃癌患病风险提高,提示检测该位点基因型有助于评估胃癌的遗传易感性;TJP1 rs 7179270 位点的基因型频率与临床病理学参数及胃癌患者手术后生存时间无显著相关性,提示TJP1 rs 7179270 位点多态性可能不参与胃癌的进展和预后;TJP1 rs 34771010、rs 28578444和rs 41280058稀有等位基因频率为0.0,推测中国福建地区人群可能无这三个位点的多态性分布。     

Relationship between LAPTM4B gene polymorphism and susceptibility of gastric cancer.

BACKGROUND: A novel gene called LAPTM4B (lysosome-associated protein transmembrane 4beta) was mapped to 8q22, and contains seven exons. The 2.25-kb messenger RNA of the gene encodes a putative lysosome-associated protein with four transmembrane regions. There are two alleles of the gene, named as LAPTM4B*1 and LAPTM4B*2. Allele *1 differs from allele *2 in that it contains only one copy of a 19-bp sequence in the 5' untranslated region (UTR), whereas this sequence is duplicated and tandemly arranged in allele *2. Studies showed that the allelic variation of LAPTM4B was associated with the genetic susceptibility of hepatocellular carcinoma but not with that of esophageal squamous cell carcinoma. This study was designed to investigate the possible association between the allelic variation of LAPTM4B and the genetic susceptibility of gastric cancer. Materials and methods: The genotype of LAPTM4B was analyzed in 350 unrelated healthy adult individuals and 214 patients with gastric cancer by utilizing polymerase chain reaction based on specific primers. The genotypic distribution of LAPTM4B was analyzed by chi(2) test. RESULTS: The allelic frequencies of the *2 were 33.88% and 24.14% in the gastric cancer group and the healthy control group, respectively, which was significantly different between the two groups (P < 0.001). There was a significant difference in the overall genotypic distribution between the patients and the controls (P = 0.023). The risk of suffering from gastric cancer was increased 1.819 times in the individuals of the *1/2 genotype [95% confidence interval (CI) 1.273-2.601] and 2.387 times in the individuals of the *2/2 genotype of LAPTM4B (95% CI 1.195-4.767) compared with the *1/1 genotype. No association between the genotypic distribution of LAPTM4B and the clinical information on patients of gastric cancer such as age, pathological type, differentiation classification of TNM, and infection of hepatitis B virus was shown. CONCLUSION: This study indicated that allele *2 of LAPTM4B might be the risk factor of gastric cancer, which could be associated with genetic susceptibility of gastric cancer.     

Genetic susceptibility and gastric cancer risk

The aim of the present paper is to review and evaluate, in a comprehensive manner, the most recent published evidence on the contribution of genetic susceptibility to gastric cancer risk in humans. We have identified all studies available in MEDLINE published up to October 2001. Only studies carried out in humans and comparing gastric cancer cases with at least 1 standard control group were included in the analysis. We were able to find 31 articles based on 25 case-control studies carried out in Caucasian, Asian and African populations. Most of the studies assess the effect of genes involved in detoxifying pathways (n = 12) and inflammatory responses (n = 7). The most widely studied is the GSTM1 null polymorphism. Only a very few studies have evaluated the risk of gastric cancer associated with genes acting on mucosa protection, oxidative damage and DNA repair. The most consistent results are the increased gastric cancer risk associated with IL1B and NAT1 variants, which may account for up to 48% of attributable risk of gastric cancer. Only polymorphisms at HLA-DQ, TNF and CYP2E genes may confer some protective effect against gastric cancer. The most important limitations that preclude definitive conclusions are (i) the lack of appropriate control of potential sources of bias (only 5 population-based studies have been published so far); (ii) the low number of cases analyzed (14 studies included fewer than 99 cases); and (iii) the low number of studies (n = 3) offering concomitant analysis of genetic susceptibility and exposure to relevant cofactors (Helicobacter pylori infection, diet and smoking). We conclude that the scientific data on the role of genetic factors in gastric cancer risk are promising. The lack of association reported so far should be considered with caution due to significant limitations in study design. Cohort studies taking into account simultaneously the different genetic and environmental factors potentially involved in gastric tumorigenesis are needed to ascertain not only the relative contribution of these factors to tumor development but also the contribution of their putative interactions.     

Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk Italian population

We performed a case-control study to examine the relationship between MTHFR C677T gene polymorphism (MTHFR677C/T) and gastric cancer susceptibility in at-risk populations in central Italy. To explore genomic DNA hypomethylation as a potential etiologic mechanism, this phenomenon was evaluated in carriers of the MTHFR677T/T genotype and carriers of the wild-type MTHFR677C/C genotype. Lymphocyte genomic DNA from 162 gastric cancer patients and 164 controls was used for MTHFR677C/T genotyping. Unconditional regression analysis with ORs and 95% CIs was used to investigate the association of the polymorphism with disease. Genomic DNA methylation status by an established enzymatic assay that measures the DNA accepting capacity of methyl groups (inversely related to endogenous methylation) was assessed in a random sample of 40 carriers of the wild-type MTHFR677C/C genotype and 40 carriers of the MTHFR677T/T genotype. The global allelic distribution was in Hardy-Weinberg equilibrium. The MTHFR677T allele was significantly associated with gastric cancer risk with an OR of 2.49 (95% CI 1.48-4.20) in heterozygous MTHFR677C/T carriers and an OR of 2.85 (95% CI 1.52-5.35) in homozygous MTHFR677T/T carriers. This risk association was retained in subgroup analyses by tumor histotype and location. Genomic DNA hypomethylation status in MTHFR677T/T carriers was significantly higher than in subjects with wild-type MTHF677C/C genotype (p = 0.012). In the studied population, MTHFR677T played the role of a moderate-penetrance gastric cancer susceptibility allele. Possession of the MTHFR677T/T genotype was significantly associated with genomic DNA hypomethylation. These findings deserve further investigation in the context of novel strategies for gastric cancer prevention.     

胃癌相关易感基因单核苷酸多态性研究进展

胃癌具有一定程度的遗传易感性,可能与人群中存在基因多态性有关.近来,胃癌易感性与基因单核苷酸多态性的相关性研究逐渐增加并取得长足进展,目前研究的基因包括细胞增殖基因、酶基因、癌基因与抑癌基因等.     

Genetic variant of PRKAA1 and gastric cancer risk in an eastern Chinese population

Published data on the association between PRKAA1 rs13361707 T > C polymorphism and gastric cancer (GCa) susceptibility were inconclusive. To derive a more precise estimation of the association, we conducted a large-scale GCa study of 1,124 cases and 1,194 controls to confirm this association in an Eastern Chinese population. Our results showed that the C allele of PRKAA1 rs13361707 increased the GC risk in the study population [CT vs. TT, odds ratio (OR) = 1.72, 95% confidence interval (CI) = 1.40–2.12; CC vs. TT, OR = 2.15, 95%CI = 1.70–2.71; CT/CC vs. TT, OR = 1.86, 95%CI = 1.53–2.26; CC vs.TT/CT, OR = 1.49, 95%CI = 1.24–1.79]. In addition, the association of C allele with an increased GCa risk was still significant in subgroups, when stratified by age, sex, tumor site, drinking and smoking status. Moreover, the findings in the present study were validated by our further meta-analysis. In summary, these results indicated that the C allele of PRKAA1 rs13361707 was a low-penetrate risk factor for GCa.