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1.
李北芳  高静 《中国肿瘤临床》2017,44(11):522-526
2014年癌症基因组图谱(The Cancer Genome Atlas,TCGA)首次将胃癌从分子水平分为四型,其中EB病毒(Epstein-Barr virus,EBV)感染型即EBV相关性胃癌(EBV-associated gastric cancer,EBVaGC)患者,可能是免疫治疗的适宜群体。在包括胃癌在内的大部分肿瘤中p53基因突变率最高,但在EBVaGC中p53基因突变率却远低于EBV阴性胃癌(EBV-negative gastric cancer,EBVnGC)。可能机制为:EBV感染是EBVaGC形成的早期事件;野生型p53蛋白与病毒即刻早期蛋白BZLF1(Z)相互作用,维持EBV潜伏感染状态和早期复制;病毒复制后期,野生型p53蛋白可在病毒产物的作用下通过泛素化等途径被降解,以上或可表明p53基因野生型对EBVaGC形成的重要性。而EBV感染诱导炎症反应,肿瘤组织中大量淋巴细胞浸润,基因组高突变率及PD-L1扩增的特征使其可能成为免疫治疗的适宜群体,也说明免疫微环境在肿瘤发生发展中的重要作用。而在EBVnGC中,多种因素导致p53基因突变率较高,使其失去正常的抑癌功能而导致肿瘤发生。本文就EBVaGC中罕见p53基因突变这一现象的可能机制进行综述。   相似文献   

2.
 目的 探讨p53基因突变以及mdm2,p53和p21蛋白表达异常在EBV相关胃癌(EBVaGC)发生发展中的作用。方法 应用免疫组化技术检测13例EBVaGC、45例临床病理资料与之匹配的EBV阴性胃癌(EBVnGC)组织中 mdm2,p53和p21蛋白的表达;PCR-SSCP银染技术结合DNA序列分析检测p53基因exon 5~8突变;RT-PCR检测EBV相关基因的表达。结果 E-BVaGC组与EBVnGC组相比,两组间mdm2,p53和p21蛋白的阳性检出率差异无统计学意义(P = 0.830 0;P = 0.791 2;P = 0.353 1),但EBVaGC组p53蛋白过表达率(15.38 %)明显低于EBVnGC组(57.78 %),两组间差异有统计学意义(P = 0.008 5)。mdm2蛋白阳性表达与p53蛋白过表达呈显著正相关(P = 0.000 8,r = 0.439 1);p21与p53蛋白共同表达率较高,但经计数资料相关性统计学分析表明两者无显著相关性(P = 0.2501,r = 0.202 5)。2例EBVnGC检测到p53基因突变,突变均位于exon 5,13例E-BVaGC和58例相应癌旁组织均未检测到p53基因突变。13例EBVaGC核抗原基因EBNA1均为阳性,潜伏膜蛋白基因LMP1均为阴性,即刻早期基因BZLF1,早期基因BARF1和BHRF1阳性率分别为46.15 %(6/13),46.15 %(6/13)和15.38 %(2/13),三者与EBVaGC组织中mdm2,p21和p53蛋白的表达均无显著相关性(P>0.05)。 结论 EBV感染以及mdm2,p53和p21蛋白表达异常与胃癌发生有关; p53基因突变可能并非胃癌组织中p53蛋白异常累积的主要原因;胃癌组织中EBV感染与p53蛋白的异常表达有关,而与mdm2和p21蛋白的异常表达以及p53基因突变无显著相关性。  相似文献   

3.
目的:观察胃癌组织中幽门螺杆菌(H.pylori)感染和EB病毒潜伏膜蛋白(EBV—LMP)的同步表达情况,探讨两者在胃癌中的相互关系。方法:80例正常胃黏膜组织和97例胃癌组织,利用HE染色对所取标本进行组织病理学诊断,EBV—LMP测定采用免疫组化sP法,H.pylori感染判定采用HE,H.pylofi—DNA PCR和血清ELISA法测定IgG抗体三种方法。结果:正常胃黏膜组织未见EBV—IMP的表达,胃癌黏膜组织EBV—LMP表达阳性率为7.2%(7/97),胃癌组织EBV—LMP表达明显高于正常胃黏膜组织,差异有统计学意义(P〈0.05)。本组病例中H.pylofi感染的胃癌黏膜组织中EBV—LMP的阳性表达率为13.5%(7/52),无H.pylori感染的胃癌组织EBV—LMP的阳性表达率为0,H.pylori感染的胃癌组织EBV—LMP表达明显高于无H.pylofi感染的胃癌组织,差异有统计学意义(P〈0.05)。结论:正常胃黏膜组织无EBV—LMP的表达,胃癌组织中EBV—LMP表达明显高于正常胃黏膜组织,H.pylofi感染胃癌组织比无H.pylori感染胃癌组织EBV—LMP呈现高表达,H.pylofi感染和EB病毒感染在胃癌的发生和发展过程中可能具有更加深在的相互关系。  相似文献   

4.
  目的   探讨甘肃省武威地区胃癌患者EB病毒(Epstein-Barr virus,EBV)感染状况及miR-101、EZH2、COX-2在EBV相关胃癌发生发展中的作用。   方法   应用组织芯片、原位杂交和免疫组织化学技术检测120例胃癌组织及相应癌旁组织中EBV小RNA(EBER)、miR-101、EZH2、COX-2的表达情况。   结果   120例胃癌组织EBV阳性率为10.0%,EBV相关胃癌有较少的淋巴结转移,好发于贲门、胃体(P < 0.05)。miR-101、EZH2、COX-2在120例胃癌组织和相应癌旁组织的阳性率差异有统计学意义(P < 0.05)。12例EBV阳性胃癌组织miR-101、EZH2、COX-2和108例EBV阴性胃癌组织3个分子的表达率差异有统计学意义(P < 0.05)。胃癌组织EBV感染和miR-101表达呈正相关,EBV相关胃癌组织miR-101表达和淋巴结转移、COX-2、EZH2表达均呈负相关(P < 0.05)。   结论   EB病毒感染与武威地区胃癌的发生有一定关系;EBV相关胃癌和EBV阴性胃癌在淋巴结转移和发生部位的差异有统计学意义;miR-101、EZH2、COX-2与EB病毒相关胃癌的发展有一定关系。   相似文献   

5.
何丹  肖琳  陈健宁  梁琼  邵春奎 《癌症》2010,29(3):304-309
背景与目的:大约有10%的胃癌组织EB病毒(Epstein-Barrvirus,EBV阳性,但EBV在胃癌发生发展中的作用尚不明确。本研究检测Fas、FasL在EBV相关胃癌(EBV-associated gastric carcinoma,EBVaGC)中的表达,及其与肿瘤细胞和肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)凋亡的相互关系。方法:采用免疫组织化学方法检测49例EBVaGC、20例EBV阴性胃癌(EBV-negative gastric carcinoma,EBVnGC)以及12例正常胃黏膜中Fas、FasL的表达,并采用TUNEL技术检测细胞凋亡指数(apoptosis index,AI)。结果:12例正常胃黏膜和69例胃癌组织的Fas阳性率分别为91.7%和76.8%,FasL阳性率分别为16.7%和58.0%,差异有统计学意义(P<0.05);Fas在EBVaGC和EBVnGC组织中的阳性率分别为71.4%和90.0%,差异无统计学意义(P>0.05)。FasL在EBVaGC和EBVnGC组织中的阳性率分别为63.2%和45.0%,差异有统计学意义...  相似文献   

6.
张朦琦  高静 《中国肿瘤临床》2018,45(10):525-528
2014年癌症基因组图谱(TCGA)将胃癌在分子水平分为四型:EB病毒感染型、基因组稳定型、染色体不稳定型及微卫星不稳定型。其中EBV相关性胃癌(Epstein-Barr virus-associated gastric cancer,EBVaGC)因具有PD-L1/2扩增/过表达的分子特性,有望成为免疫治疗的适宜群体而受到关注。了解EBVaGC的分子特征对胃癌机制研究及指导治疗有重要意义。目前,EBVaGC分子特征包括PD-L1/2过表达、PIK3CA突变、ARID1A突变、DNA超甲基化及TP53低突变等;相应地,可能的治疗策略有靶向免疫检查点抑制剂、靶向PI3K/AKT通路抑制剂及抗病毒治疗等。本文就上述EBVaGC的重要分子特征及可能的治疗策略进行综述。   相似文献   

7.
[摘要] 目的:探讨青岛地区汉族人群lncRNA H19 单核苷酸多态性(SNP)与胃癌和EBV相关胃癌(EBVaGC)易感性的关系。方法:收集青岛地区汉族人群2015 年1 月至2018 年10 月青岛大学附属医院经病理科确诊为胃癌的新鲜组织或陈旧的石蜡包埋胃癌组织病理标本共225 例,为胃癌组;依据原位杂交法对EBV编码的小分子非多聚腺苷酸(EBER1)转录检测结果再将胃癌组分为2 亚组:EBVaGC 组70 例,EBVnGC组155 例;同时选择青岛大学附属医院门诊健康体检者200 例为对照组。提取EBVaGC、EBVnGC 组织及健康人群外周血标本的DNA,根据HaploView 软件常规设置原则(MAF>0.05;r2>0.8)筛选出rs217727、rs2735971、rs2839698 和rs3741216 四个H19 的TagSNPs。利用Taq-Man MGB 等位基因分型试剂盒对各SNP位点基因进行基因分型,并进行基因多态性检测。结果:所取标本的H19 SNPs 均符合Hardy-Weinberg 平衡。与对照组比较,胃癌组H19 rs217727位点TT 基因型的发病风险显著增加(χ2=9.073, P=0.003, OR=1.999, 95% CI=1.271~3.143),等位基因T 的分布也明显增高(χ2=13.475, P=0.001, OR=1.661, 95% CI=1.266~2.180);H19 rs2839698 位点TC、CC基因型人群可显著增加胃癌的发病风险(χ2=9.407,P=0.002; χ2=6.517, P=0.011),携带C等位基因人群罹患胃癌的风险明显增加(χ2=6.163, P=0.013, OR=1.417, 95% CI=1.076~1.867;χ2=9.542, P=0.02, OR=2.070, 95% CI=1.298~3.302)。但胃癌组H19 rs2735971 和rs3741216 位点基因多态性与对照组比较差异不明显(均P>0.05);EBVaGC 和EBVnGC 组中H19 的4 个位点基因多态性分布差异均无统计学意义(均P>0.05)。结论:H19 rs217727、rs2839698 基因多态性可能与胃癌发病风险有关,携带TT 基因型C等位基因和人群胃癌的发病风险明显升高;H19 SNP的多态性与EBVaGC的发病风险无明显相关。  相似文献   

8.
胃癌组织中EB病毒的检测及其增殖期基因的表达   总被引:4,自引:0,他引:4  
目的;探讨EB病毒(Epsteirt-Barr virus.EBV)感染与胃癌发生的关系及其增殖期基因在EBV阳性胃癌发生中的作用。方法:应用聚合酶链反应(PCR)-Southern杂交检测185例胃瘟组织和相应癌旁组织中特异性EBVDNA片段.PER阳性标本用原位杂交(ISH)技术检测石蜡切片组织中EBV犏码小RNA1(EBER1)的表达.以确定EBV阳性胃癌一再应用RT-PCR和Southern杂交技术检测EBV增殖期基因(即刻早期基困BZLF1、BRLF1,早期基因BARF1、BHRF1.晚期基冈BcLF1、BLLF1)的表达.结果:13例胃癌组织EBV阳性(7.03%),癌旁组织未检测到EBV感染.胃癌和癌旁组织中EBV阳性纺有显著性差异(X^2=11.0769.P=0.0009)。EBV阳性和阴性胃癌在年龄、病理类型、临床分期、淋巴结转移和发生部位的差别均无显著性(P=0.973,0.141,0.259,0.586,0.062).但性别之间的差异有显著性,男性EBV阳性率高于女性(X^2=52317.P=0.021)。增殖期基因中即刻早期基因BZLF1有6例表达阳性.而BRLF1均为阴性;早期基因中有6铡BARF1表达阳性.2例BHRF1表达阳性;晚期基因BcLF1有7倒表达阳性.而BLLF1均为阴性。结论:EBV感染与胃癌的发生有一定的相关性.部分EBV阳性胃癌组织中存在EBV增殖性感染.早期基因BARF1和BHRF1在EBV阳性胃癌发生过程中可能有重要作用。  相似文献   

9.
目的: 探讨Toll样受体(TLR)家族成员TLR2基因启动子区-196~-174 del和TLR4基因 Thr399Ile位点多态性与EBV相关胃癌(EBVaGC)及EBV阴性胃癌(EBVnGC)易感性的关系。方法:采用PCR技术检测52例EBVaGC,157例EBVnGC以及94例正常对照人群TLR2(-196~-174 del)基因多态性;PCR-限制性片段长度多态性(PCR-RELP)技术检测50例EBVaGC,67例EBVnGC以及71例正常对照TLR4 Thr399Ile位点基因型及等位基因分布;分析2种基因多态性与EBVaGC及EBVnGC易感性的关系。结果:胃癌组与对照组比较TLR2(-196~-174 del)基因型分布无显著差异(χ2=3.180,P=0.075),胃癌组del等位基因频率明显高于对照组(χ2=4.875, P=0.027),del等位基因携带者的罹患危险性明显高于非携带者(OR=1.491,95%CI=1.045~2.126);EBVaGC组和EBVnGC组中,TLR2(-196~-174 del)3种基因型以及del等位基因频率差异无统计学意义(χ2=0.05,P=0.867)。EBVaGC组、EBVnGC组和正常对照组中均未发现TLR4基因Thr399Ile位点的多态,其基因型分布及等位基因频率差异均无统计学意义(P>0.05)。结论:TLR2(-196~-174 del)等位基因可能是胃癌发病危险因素,且在EBVaGC和EBVnGC两种胃癌发生中产生相同的影响。未发现TLR2(-196~-174 del)和TLR4基因Thr399Ile基因型分布与EBVaGC的易感性相关。  相似文献   

10.
[目的]探讨EBV感染和p53基因异常在胃癌发生发展中的病因学作用.[方法]应用免疫组化技术检测13例EBV相关胃癌(EBV associated gastric carcinoma,EBVaGC),45例临床指标与之匹配的EBV阴性胃癌(EBV negative gastric carcinoma,EBVnGC)以及58例相应癌旁组织中p53蛋白的表达;PCR-SSCP银染技术检测p53基因exon 5~8突变情况.[结果]①胃癌组p53蛋白阳性率为86.2%(50/58),而相应癌旁组织均为阴性,胃癌组p53蛋白的阳性率明显高于癌旁组织组,两组间有极显著性差异(P=0.0000).②EBVnGC p53蛋白阳性率为86.7%(39/45),过表达率为57.8%(26/45);EBVaGC p53蛋白阳性率为84.6%(11/13),过表达率仅为15.4%(2/13).两组间p53蛋白的阳性检出率无明显差异(P=0.7912),但EBVaGC组p53蛋白过表达率明显低于EBVnGC组,两组间有显著性差异(P=0.0085).③2例EBVnGC检测到p53基因突变,突变均位于exon 5,13例EBVaGC和58例相应癌旁组织均未检测到p53基因突变.[结论]p53基因异常与胃癌的发生密切相关,EBVaGC组织中存在p53蛋白的表达和过表达,但p53蛋白的异常累积可能并非p53基因突变所致.  相似文献   

11.
We studied the comprehensive DNA methylation status in the naturally derived gastric adenocarcinoma cell line SNU‐719, which was infected with the Epstein–Barr virus (EBV) by methylated CpG island recovery on chip assay. To identify genes specifically methylated in EBV‐associated gastric carcinomas (EBVaGC), we focused on seven genes, TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1, based on the results of methylated CpG island recovery on chip assay. We confirmed DNA methylation of the genes by methylation‐specific PCR and bisulfite sequencing in SNU‐719. The expression of the genes, except for BCL7A, was upregulated by a combination of 5‐Aza‐2′‐deoxycytidine and trichostatin A treatment in SNU‐719. After the treatment, unmethylated DNA became detectable in all seven genes by methylation‐specific PCR. We verified DNA methylation of the genes in 75 primary gastric cancer tissues from 25 patients with EBVaGC and 50 EBV‐negative patients who were controls. The methylation frequencies of TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1 were significantly higher in EBVaGC than in EBV‐negative gastric carcinoma. We identified seven genes with promoter regions that were specifically methylated in EBVaGC. Inactivation of these genes may suppress their function as tumor suppressor genes or tumor‐associated antigens and help to develop and maintain EBVaGC.  相似文献   

12.
DNA hypermethylation may play a primary role in the genesis of Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) (EB-VaGC). Methylation-specific PCR targeting CpG-islands demonstrated markedly increased methylation of specific genes, such as p14, p15 and p16 genes, in EBVaGC in vivo . A high frequency of methylation was observed in an EBVaGC strain of severe combined immunodeficiency mice, and the expression of methylated genes in the strain was apparently lower than the expression of the unmethylated genes in EBV-negative GC strains. Although over-expression of DNA methyltransferases ( DNMTs ) is known to be associated with some human cancers, real-time PCR demonstrated that DNMTs expression was suppressed in EBVaGC. The DNA methylation of specific genes, independently of DNMTs expression, may be important in the development of EBVaGC. (Cancer Sci 2003; 94: 76–80)  相似文献   

13.
Epstein-Barr virus (EBV) has been linked to gastric carcinoma (GC) with worldwide geographical variations attributable to types and variants of EBV. Here, we compare EBV strains between EBVaGC and healthy donors in Latin America, a high frequency area for EBVaGC. Tumor samples from 73 EBVaGC cases and throat washings from 329 healthy adults were examined for types 1 and 2 EBV and polymorphism at BamHI-F and BamHI-W1/I1 boundary regions and XhoI restriction site in LMP1 gene. Type 1 and prototype F of BamHI- F polymorphism accounted 59 (81%) and 69 (95%) of EBVaGC cases and 257 (78%) and 267 (81%) of healthy donors, respectively. Types I and "i" of BamHI W1/I1 polymorphism accounted 2 (3%) and 62 (85%) of EBVaGC and 85 (26%) and 170 (52%) of healthy donors, respectively (p<0.001). XhoI+ and - polymorphism accounted 60 (82%) and 4 (5%) of EBVaGC and 142 (43%) and 92 (28%) of healthy donors, respectively (p<0.001). Cosegregation analysis demonstrated that most of the 62 type "i" EBVaGC cases harbor XhoI+ strain (81%). However, among 143 type "i" healthy adults, both XhoI polymorphism were present in relatively similar frequencies (XhoI+ 58% and XhoI- 42%) (OR 9.0; 95% CI 1.2-69). Our findings are against to the proposed hypothesis that EBV strains are geographically but not disease-restricted. We conclude that most of the EBVaGC cases harbor a distinctive EBV strain (type "i"/XhoI +), but in healthy donors, this strain was as common as other strains. This finding is contrary to the proposed hypothesis that EBV strains are geographically but not disease-restricted and identified a healthy population group that share the same strain that predominate in EBVaGC cases.  相似文献   

14.
Promoter hypermethylation of various tumor-related genes is extremely frequent in Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC). To investigate the significance of the promoter methylation in EBVaGC, we focused on one of the important proteins in the carcinogenesis of the stomach, E-cadherin. Methylation-specific PCR analysis (MSP) was applied to surgically resected gastric carcinomas, together with immunohistochemistry, PCR-based analysis of mutations and allelic loss, and site-specific MSP of E-cadherin gene. By MSP, nearly all of the carcinomas showed aberrant methylation of E-cadherin promoter in EBVaGC (21/22), and the frequency of this aberration was significantly higher than that in EBV-negative gastric carcinoma (GC; 45/81; p = 0.0003). According to immunohistochemistry of E-cadherin, the frequency of abnormal staining pattern in EBVaGC (87%) was comparable to that in the diffuse type (80%), but higher than that in the intestinal type of EBV-negative GC (47%). Promoter methylation was well correlated with abnormal staining pattern in EBVaGC, but not in EBV-negative GC. Neither mutation nor allelic loss of E-cadherin was observed in EBVaGC. Methylation status of E-cadherin within each carcinoma was heterogeneous as far as examined. Thus, in addition to the known association involving p16, we determined that promoter methylation-mediated silencing of E-cadherin gene was also closely associated with the development of EBVaGC, although it becomes heterogeneous within a given tumor along its progression.  相似文献   

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Epstein–Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8–9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.  相似文献   

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