散发性结直肠癌染色体10q23～24区域杂合缺失分析

目的抑癌基因的杂合缺失（LOH）被认为是结直肠癌形成的通路之一,本实验拟通过对染色体10q23～24区的LOH分析,发现高频杂合缺失区域并筛查与结直肠癌相关的抑癌基因。方法7个荧光标记的微卫星引物（围绕D10S185位点）与83例结直肠癌的肿瘤和正常组织进行聚合酶链反应（PCR）反应。产物在ABI Prism377自动荧光测序仪进行电泳,以GeneSean3．1和Genotyper2．1软件进行扫描以及杂合缺失分析LOH。与临床病理因素之间的关系比较采用X^2检验。结果7个位点平均杂合缺失率为36．11％,以D10S583位点最高,达54．84％;最低是D10S205,21．3％。发现两个高频杂合缺失区域：一个在D10S583和D10S185之间,大约0．9cM（10q23．33）的距离;另一个在D10S1709和D10S1265位点之间,大约1．5cM（10q24．2～24．31）的距离。D10S1265位点的杂合缺失与Dukes分期显著相关,其余位点与临床病理因素均无显著相关。结论在散发性结直肠癌10q23-24发现了两个高频LOH区域：10q23．33和10q24．2～24．31。除对磷脂酶同族蛋白（PTEN）基因外,10q上可能存在与散发性结直肠癌相关的其他抑癌基因。     

胃癌患者6号染色体长臂遗传不稳定性

目的研究中国人胃癌6号染色体长臂微卫星不稳定性（microsatellite instability，MSI）和杂合性缺失（loss of heterozygosity，LOH）状况及与临床病理特征之间的联系。方法采用PCR-SSLP-银染方法对27例胃癌组织及其相应正常组织6号染色体长臂（6q）不同位置的4个位点进行MSI和LOH检测。结果27例信息个体中16例检测到一个或多个位点MSI，平均MSI频率59．2％；11例不具MSI的信息个体中7例存在1个或更多位点LOH，平均频率63．6％。MSI和LOH频发位点均为D6S434（6q16．3-q21）和D6S404（6q16．3-q23）。MSI和LOH在高分化胃癌和低分化胃癌各个时期均有发生．但高分化胃癌中高水平MSI（MSI-H）发生有增高趋势。结论MSI和LOH发生率与年龄、性别、组织分化程度、病理分期及发病部位等临床指标虽然无明显相关，但6q等位基因缺失关键区域与其它国家、地区相似，进一步证实6q上该区可能存在与胃癌相关的肿瘤抑制基因。     

High frequency loss of heterozygosity on the long arms of chromosomes 13 and 14 in nasopharyngeal carcinoma in Southern China

目的：分析鼻咽癌（NPC）13号染色体长臂（13q）和14号染色体长臂（14q）上21个位点的等位基因杂合子丢失（LOH）,并分析这些位点的LOH与NPC临床病理及EBV感染的关系。方法：用聚合酶链反应（PCR）为基础的微卫星多态性分析技术结合基因扫描和基因绘图技术对60例NPC进行LOH分析。结果：13q染色体发生一个或多个位点LOH频率为78％,高频率LOH（大于30％）位点集中于13q12.3-q14.3和13q32附近。14q染色体发生至少一个位点LOH的频率为80％,高频率丢失位点集中于14q11-q13、1q421-q24和14q32附近。13q31-q32位点的LOH与低滴度血清EBV EA/IgA有关;14q染色体的LOH与NPC细胞的分化差有关。结论：华南地区鼻咽癌在13q和14q染色体发生高频率的LOH,这些缺失区可能存在多个在NPC发生发展过程中起重要作用的肿瘤抑制基因。     

High frequency loss of heterozygosity in the region of the DBH locus in bladder cancer

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Screening of tumor suppressor genes on lq31.1-32.1 in Chinese patients with sporadic colorectal cancer

Background As a model for both multistep and multipathway carcinogenesis, colorectal neoplastic progression provides paradigms for researching both oncogenes and tumor suppressor genes (TSGs). However, the mechanism of colorectal cancer (CRC) is not completely understood, and many genes may be involved in the colorectal carcinogenesis. The purpose of this study was to screen for the potential TSGs on chromosome lq31.1-32.1 in Chinese patients with sporadic colorectal cancer, to explore whether colorectal cancer in the Chinese population has unique genetic alterations and determine whether other putative TSGs exist and contribute to colon carcinogenesis. Methods Six polymorphic microsatellite markers, at a density of approximately one marker in every 1.6 cM, were chosen for refined loss of heterozygosity (LOH) mapping of lq31.1-32.1. Eighty-three colorectal cancer patients' tumor and normal DNA were analyzed via polymerase chain reaction (PCR) for these microsatellite markers. PCR products were eletrophoresed on an ABI 377 DNA sequencer. Genescan 3.1 and Genotype 2.1 software were used for LOH scanning and analysis. On the basis of refined LOH mapping results, we undertook a microarray-based expression screening to identify tumor association genes in 19 of the CRC cases. Results The average LOH frequency of lq31.1-32.1 was 24.41%, with the highest frequency of 36.73% (18/49) at D1S2622, and the lowest of 16.42% (11/67) at D1S412. A minimal region of frequent deletion was located within a 2 cM genomic segment at D1S413-D1S2622. There was no significant association between LOH of any marker in the studied regions and the clinicopathological data (patient sex, age, tumor size, growth pattern, or Dukes stage). On the basis of refined mapping results, we chose 25 genes located in the D1S413-D1S2622 (lq31.3-32.1) region and presented a microarray-based high throughput screening approach in 19 sporadic CRC cases to identify candidate CRC related tumor suppressor genes. This study found 4 significantly down-expressed genes, including CSRP1, LMOD1, PPP1R12B and CFHL3. There was no significant association between expression levels of CFHL3, CSRP1, LMOD1, PPPIR12B and the clinicopathological data. By database searching, CSRP1 was hypothesized to be a colorectal cancer related tumor suppressor gene. Conclusions Through detailed deletion mapping, we found that the lq31.3-32.1 region might harbor one or more colorectal cancer related tumor suppressor gene(s). And by microarray-based high-throughput screening of candidate genes located in this region and by subsequent database searching, we present the first evidence that CSRP1 might be involved in the progression of CRC.     

散发性结直肠癌的染色体不稳定研究及其临床病理意义

目的 探讨散发性结直肠癌（sporadic colorectal cancer,SCRC）的DNA倍体异常和染色体畸变的数目、部位及其与临床病理特征之间的关系.方法 将40例SCRC肿瘤标本制备成单细胞悬液,经染色后进行流式细胞术（flow cytometry,FCM）检测,分析肿瘤细胞DNA倍体;采用比较基因组杂交技术（comparative genomic hybridization,CGH）在全基因组水平对40例SCRC进行染色体畸变检测.结果 40例SCRC患者标本中,二倍体的比例为42.5%,异倍体为57.5%,DNA倍体与TNM分期有密切关系,分期越高,异倍体的比例越高,差异有统计学意义（P＜0.05）.CGH检测的所有病例均有不同程度的染色体畸变,平均每例畸变数为7.55,常见的染色体扩增区域有：20q、12q、13q、7p等,常见缺失区域有18q、5q、4q、8p等.TNM分期中Ⅲ～Ⅳ期SCRC的染色体畸变数高于Ⅰ～Ⅱ期（6.00±2.76 vs 8.70±2.84,P＜0.05）.不同肿瘤部位、分化程度、组织学类型SCRC的DNA倍体差异无统计学意义（P ＞0.05）.二倍体肿瘤的染色体畸变数明显少于异倍体肿瘤（6.35±3.35 vs 8.43±2.59,P＜0.05）.结论 染色体不稳定在SCRC中普遍存在,是SCRC病情进展的基础,染色体畸变比DNA倍体异常更为常见.     

散发性结直肠癌3号染色体等位基因杂合缺失

目的 了解散发性结直肠癌（SCRC）3号染色体等位基因杂合缺失（LOH）发生情况。探讨其与临床病理特征间的关系,并对3号染色体上可能的SCRC相关基因进行初步定位。方法 用覆盖3号染色体的13个微卫星标记对83例散发性结直肠癌进行LOH扫描分析。结果 3号染色体至少有两个位点发生LOH者占39%（29/74）,3p所选4个位点中至少有一个发生LOH者占37%（27/74）,3q所选9个位点中至少有一个发生LOH者占53%（39/74）。整条染色体上以D3S1300（3q14.2)位点LOH率最高,达54%（23/43）。3qLOH在远端结直肠癌较近端高发,3q及D3S1300LOH阳性肿瘤多表现为浸润型生长和局部侵犯,并多发于大于50岁的老年患者。结论 3号染色体存在散在分布及区域性高频等位基因LOH,并与SCRC临床病理资料相关,提示其上SCRC相关基因的存在。高频LOH位点D3S1300的发现,提示3p14.2附近区域的FHIT基因可能作为肿瘤抑制基因在结直肠癌的发生发展中发挥作用。     

Screening of tumor suppressor genes on 1q31.1-32.1 in Chinese patients with sporadic colorectal cancer

Background As a model for both multistep and multipathway carcinogenesis, colorectal neoplastic progression provides paradigms for researching both oncogenes and tumor suppressor genes （TSGs）. However, the mechanism of colorectal cancer （CRC） is not completely understood, and many genes may be involved in the colorectal carcinogenesis. The purpose of this study was to screen for the potential TSGs on chromosome 1q31.1-32.1 in Chinese patients with sporadic colorectal cancer, to explore whether colorectal cancer in the Chinese population has unique genetic alterations and determine whether other putative TSGs exist and contribute to colon carcinogenesis. Methods Six polymorphic microsatellite markers, at a density of approximately one marker in every 1.6 cM, were chosen for refined loss of heterozygosity （LOH） mapping of 1q31.1-32.1. Eighty-three colorectal cancer patients＇ tumor and normal DNA were analyzed via polymerase chain reaction （PCR） for these microsatellite markers. PCR products were eletrophoresed on an ABI 377 DNA sequencer. Genescan 3.1 and Genotype 2.1 software were used for LOH scanning and analysis. On the basis of refined LOH mapping results, we undertook a microarray-based expression screening to identify tumor association genes in 19 of the CRC cases. Results The average LOH frequency of 1q31.1-32.1 was 24.41%, with the highest frequency of 36.73% （18/49） at D1S2622, and the lowest of 16.42% （11/67） at D1S412. A minimal region of frequent deletion was located within a 2 cM genomic segment at D1S413-D1S2622. There was no significant association between LOH of any marker in the studied regions and the clinicopathological data （patient sex, age, tumor size, growth pattern, or Dukes stage）. On the basis of refined mapping results, we chose 25 genes located in the D1S413-D1S2622 （1q31.3-32.1） region and presented a microarray-based high throughput screening approach in 19 sporadic CRC cases to identify candidate CRC related tumor suppressor genes. This study found 4     

胃癌染色体1q21等位基因杂合性缺失的精细定位

目的 精细定位胃癌染色体1q21等位基因杂合性缺失及其常见缺失区域,并初步探讨1q21等位基因杂合性缺失在胃癌发生发展中的作用.方法 采用1q21区域7个高密度微卫星多态性标志结合PCR技术.精细分析了30例配对新鲜胃癌手术标本中胃癌染色体等位基因杂合性缺失的情况,利用X2检验和四格表确切概率法初步探讨了1q21等位基因杂合性缺失与胃癌临床特征的关系.结果 30例胃癌标本中,有18例存在等位基因杂合性缺失,占60%(18/30),7个微卫星位点D1S514、D1S2696、D1S498、D1S305、D1S2624、D1S2635和D1S2707的杂合性缺失频率分别为13.3%、10%、20%、23.3%、33.3%、40%和23.3%.常见高频率杂合性缺失区域位于D1S2624-D1S2707之间,即共同缺失区在D1S2635附近;胃癌染色体1q21等位基因杂合性缺失与病人的年龄、性别、胃癌原发灶的部位、癌细胞分化程度及临床分期比较差异没有湿著性意义(P>0.05);但是,胃癌染色体1q21等位基因杂合性缺失与胃癌有无淋巴结转移比较差异有显著性意义(P<0.05).结论 胃癌细胞染色体1q21存在较高频率的等位基因杂合性缺失,D1S2635附近可能存在与胃癌发生密切相关的肿瘤抑制基因.     

食管鳞状细胞癌染色体13q11-12杂合性丢失

目的分析食管鳞状细胞癌(esophageal squamous cell carcinoma,ESCC)在13号染色体长臂11-12区(13q11-12)上的等位基因杂合性丢失(LOH),以期寻找13q11-12区上可能存在的与食管鳞状细胞癌有关肿瘤抑制基因的缺失区域。方法用9个位于13q11-12区的微卫星标志物,对56例ESCC患者组织切片激光显微切割后,进行PCR-LOH分析;56例ESCC患者包括34例有上消化道癌家族史,22例无上消化道癌家族史。结果56例ESCC患者中,49例(87.5%)显示一个或更多位点LOH;并发现一个LOH高频率区,位于位点D13S787和D13S221之间,物理距离仅有1.83 Mb;在位点D13S1236有上消化道癌家族史组LOH为89%,明显高于无上消化道癌家族史组53%(P=0.031<0.05),差异有显著性意义。结论研究提示染色体13q11-12的LOH可能在食管癌发生、发展中起重要作用;在染色体13q11-12区上,可能存在一个或多个与ESCC发生发展有关的肿瘤抑制基因(TSG)。     

结直肠癌中DPC4/SMAD4基因杂合性缺失及生物学意义

目的分析我国散发性结直肠癌肿瘤组织中,DPC4/SMAD4基因杂合性缺失的发生情况.方法利用D18S46、D18S363、D18S474、D18S535和D18S877共5个跨DPC4基因区域的微卫星位点,采用微卫星分析方法,对25例散发性结直肠癌相关位点的杂合性缺失(LOH)进行了分析.结果至少1个位点呈多态性的病例为l00%,DPC4/SMAD4基因LOH发生率为60%.结论等位基因杂合性缺失是中国人散发性结直肠癌中DPC4基因失活的重要机制.     

胶质母细胞瘤1号染色体杂合性丢失的初步研究

目的寻找胶质母细胞瘤(GBM)1号染色体上可能存在肿瘤抑制基因的杂合性丢失(LOH)区域,为发现和定位肿瘤抑制基因提供线索和依据。方法应用聚合酶链反应(PCR)方法,采用荧光标记的引物和377型DNA自动序列分析仪,分析了21例GBM1号染色体上31个微卫星多态性标记的LOH。结果在52%(11/21例)GBM的1号染色体上观察到了LOH,在20%(94/463)可提供信息位点存在LOH。其中1p的LOH率高于1q,1p和1q的LOH率分别为43%(9/21)、33%(7/21)。1p上各微卫星位点的LOH率均小于30%。在1q的下列位点上检测到了较高LOH率1q24-1q25上的D1s218(31.6%)、1q32.3-1q43上的D1s2785(31.6%)-D1s2842(37.5%)。结论染色体1p在GBM的分子发病机制中并不重要,而染色体1q上遗传物质的分子遗传学变化可能在GBM的发生发展中起着重要作用,染色体1q24-1q25上的D1s218和1q32.3-1q43上的D1s2785-D1s2842位点间区域可能存在与GBM有关的肿瘤抑制基因。     

应用聚合酶链反应-单链构象多态性分析检测散发性乳腺癌EMSY基因的突变

目的了解EMSY基因在散发性乳腺癌组织中的突变情况,探讨EMSY基因突变与散发性乳腺癌的关系。方法收集72例散发性乳腺癌组织及18例乳腺良性肿瘤患者的肿瘤组织,常规酚-氯法抽提组织DNA,并应用聚合酶链反应-单链构象多态性分析（PCR—SSCP）的方法,扩增其EMSY基因的20个外显子,然后根据构象改变来分析此基因突变情况。结果72例散发性乳腺癌组织以及18例乳腺良性肿瘤组织中,6例样本存在第9外显子SSCP条带的异常改变,测序结果为第9外显子区GCA（丙氨酸）中的A杂合性缺失,突变率为8．3％（6／72）。结论本课题研究提示广西散发性乳腺癌中存在着EMSY基因第9外显子的缺失突变,并且在乳腺癌患者中突变率高于乳腺良性肿瘤患者。     

散发性大肠癌中hMSH2基因突变研究

目的：探讨错配修复基因hMSH2在散发性大肠癌发生中的作用。方法：应用酚／氯仿法提取44例结直肠癌组织及其相应正常黏膜组织的DNA，用聚合酶链反应和单链构象多态性分析（SSCP）、DNA测序等方法对基因hMSH2外显子5、6、13、15进行突变情况检测，并结合临床病理资料进行分析。结果：44例散发性大肠癌患者中，2例发生hMSH2基因突变，突变率为4．54％。不同临床病理分期的hMSH2基因突变率差异无统计学意义（P〉0．05）。结论：hMSH2基因可能在散发性大肠癌发生过程中起到一定作用，hMSH2基因突变与散发性大肠癌的临床病理分期无关。     

原发性肝癌患者17号和16号染色体等位基因杂合性丢失的研究

目的 研究肝癌１７号和１６号染色体特定区域等位基因杂合性丢失（ＬＯＨ）发生情况,并探讨ＬＯＨ与肝癌的临床病理和乙型、丙型肝炎病毒感染的关系。方法 用聚合酶链反应、微卫星多态性分析技术检测１７号和１６号染色体ＬＯＨ。结果 １７号染色体６个位点在至少一个位点发生ＬＯＨ的有３１例（８２％）,其中Ｄ１７Ｓ５２０（１７ｐ１２－１３．３）和ＴＰ５３（１７ｐ１３．１）位点ＬＯＨ频率大于５０％;１７ｑ所选４个位点     

增强子结合蛋白家庭的一个新基因HP8定位于人19号染色体长臂13.1-13.2区带

目的:探讨增强子结合蛋白(C/EBP)家族一个新基因HP8的人染色体定位.方法:按常规方法制备分裂期人淋巴细胞切片,用生物素标记HP8基因 3’-端 2.1kb cDNA作探针,进行荧光原位杂交(FISH).对FISH信号及染色体上DAPI结合条带同时拍照,二者重迭信号进行计数,结果:100个有丝分裂图中,有72个显示阳性信号位于同一对染色体,并且无其他非特异性杂交带,杂交效率约为70%.参照DAPI结合条带,阳性信号位于人19号染色体长臂13.1-13.2区带.结论:HP8基因定位于人19号染色体长臂 13.1-13.2区带.     

尿脱落细胞6号染色体长臂的微卫星改变诊断膀胱肿瘤

目的：探讨尿脱落细胞6q的微卫星改变(MA)在膀胱肿瘤早期诊断中的应用价值，并研究6q的杂合性缺失(LOH)与膀胱肿瘤的关系．方法：应用6q21区域附近D6S404，D6S434微卫星标志，以PCR—SSLP—银染法对31例膀胱肿瘤的尿脱落细胞与肿瘤组织进行微卫星分析．结果：64．5％的肿瘤组织和58．1％的尿脱落细胞发生MA;10例非膀胱肿瘤对照未出现MA；检出率与肿瘤分期，分级无相关性；肿瘤组织D6S404 LOH发生率35．5％，D6S434 LOH发生率22．6％．结论：尿脱落细胞微卫星分析有早期诊断意义；6q21区域附近可能存在与膀胱肿瘤相关的肿瘤抑制基因．     

胶质母细胞瘤染色体13q上肿瘤抑制基因存在的可能性

目的寻找胶质母细胞瘤(glioblastoma,GBM)13号染色体上可能存在肿瘤抑制基因的杂合性丢失 (LOH)区域,为发现和定位肿瘤抑制基因(TSG)提供线索和依据。方法应用聚合酶链反应(PCR)方法,采用 荧光标记的引物和377型DNA序列自动分析仪,分析了20例GBM13号染色体上14个微卫星多态性标记的 LOH。结果在60％GBM的13号染色体上观察到LOH,在45.8％可提供信息位点存在LOH。其中13q的 LOH率明显高于13p,13q和13p的LOH率分别为60％、27％。在13q上的下列位点上检测到较高的LOH率 (＞50％)13q14.1-14.3上D13S153,13q12-14.2上的D13S217-D13S263,13q21.2-32上的D13S156-D13S265。 结论13号染色体可能在GBM的分子发病机制中发挥着重要作用,在13q14.1-14.3上的D13S153位点、13q 12-14.2上的D13S217-D13S263和13q21.2-32上的D13S156-D13S265间区域可能存在多个与GBM相关的肿瘤 抑制基因,可能包括RB1以及不同于RB1的其他肿瘤抑制基因。     

19号染色体微卫星杂合性缺失与原发性胃癌的临床关系

目的:研究19号染色体短臂微卫星不稳定性(microsatellite instability,MSI)及杂合性缺失(loss of heterozygosity,LOH)与胃癌临床病理特征之间的关系,探讨19号染色体短臂微卫星MSI和LOH的主要临床意义.方法:采用PCR-SSLP-银染方法扩增79例原发性胃癌及正常组织标本中19号染色体短臂不同位置的7个点,PCR产物经聚丙烯酰胺凝胶电泳分离,运用Genescan软件和Genotyper软件分析MSI和LOH,然后进一步分析微卫星LOH与原发性胃癌的临床关系.结果:79例胃癌患者中,至少有1种微卫星发生LOH,其频率为31.18%(27/79),在所有微卫星中,D19S591和D19S565的LOH发生率分别为60.32%(38/63)和48.15%(26/54),高于其他微卫星的LOH.LOH高频率与原发性胃癌的临床分期及远处转移相关,且随着恶性程度增加LOH频率也增加(P＜0.05),而MSI与胃癌临床病理之间相关性不大.结论:19p高频率的LOH与原发性胃癌的临床分期和远处转移相关,且LOH高频率提示在该区域可能存在肿瘤抑癌基因,其与胃癌的发生及进展相关.     

Loss of heterozygosity on chromosome 22 in sporadic schwannoma and its relation to the proliferation of tumor cells

Background Schwannoma is the tumor arising mainly from the cranial and spinal nerves. Bilateral vestibular schwannoma is the hallmark of neurofibromatosis type 2 (NF2). The NF2 gene has been cloned with comprehensive analysis of its mutations in schwannoma. However, most studies focused on vestibular schwannoma. There are differences in proliferation of tumor cell and ultrastructure between vestibular and spinal schwannomas. It is unknown whether genetic alterations in vestibular schwannoma are different from those in non-vestibular schwannoma. We analyzed the loss of heterozygosity (LOH) on chromosome 22 in patients with sporadic schwannoma including vestibular and spinal schwannomas and correlated this genetic alteration with tumor proliferation. Methods In 54 unrelated patients without clinical NF1 or NF2, 36 patients had sporadic vestibular schwannoma, and 18 dorsal spinal root schwannoma. Four highly polymorphic linkage to NF2 gene microsatellite DNA markers (D22S264, D22S268, D22S280, CRYB2) were used to analyze LOH. The proliferative index was evaluated by Ki-67 and proliferative cell nuclear antigen (PCNA) immunostaining. Student’s t test was used to analyze the difference of the proliferative index between schwannoma with LOH and that without LOH. The difference of the frequency of LOH in vestibular and spinal schwannomas was investigated by the chi-square test. Results Twenty-three schwannomas (42.6%, 23/54) showed allele loss. The frequency of LOH in vestibular schwannoma was significantly higher than that in spinal schwannoma (χ2=5.14, P&lt;0.05). The proliferative index of schwannoma with LOH was significantly higher than that without LOH (tki-67=2.97, P=0.0045; tPCNA=2.93, P=0.0051). Conclusions LOH on chromosome 22 is a frequent event in the tumorigenesis of sporadic schwannoma. And, there is a correlation between LOH on chromosome 22 and proliferative activity in schwannoma. The frequency of LOH in vestibular schwannoma is significantly different from that in spinal schwannoma.