1、HNPCC的突变筛查的突变筛查Contents1.1.研究背景研究背景2.2.材料与方法材料与方法3.3.结果及讨论结果及讨论研究背景研究背景介绍 何为何为HNPCCHNPCC？常染色体显性遗传病；常染色体显性遗传病；5-10%5-10%发生率；发生率；MMRMMR缺陷引起缺陷引起 如何研究？如何研究？临床标准；选择临床标准；选择MLH1MLH1和和MSH2MSH2基因筛查突变基因筛查突变 研究现状研究现状欧洲多，亚洲少欧洲多，亚洲少90%90%突变出现在突变出现在MLH1MLH1和和MSH2MSH2无热点突变无热点突变研究背景介绍 临床标准临床标准Amsterdam I&IIAmsterda
2、m I&II；BethesdaBethesda；数据库数据库最权威最权威InSightInSight (http:/www.insight-group.orghttp:/www.insight-group.org)研究的意义是什么？研究的意义是什么？遗传性疾病，早预防早治疗遗传性疾病，早预防早治疗中国研究较少中国研究较少希望找到亚洲或中国的热点突变希望找到亚洲或中国的热点突变为中国的临床检测提供指导为中国的临床检测提供指导材料与方法材料与方法筛选98个疑似HNPCC病人根据临床标准：Bethesda,Amsterdam和复旦标准外周血样提取PCR测序突变筛查突变判定新突变及热点突变筛选文献In
3、Sight数据库结果与讨论结果与讨论临床资料归纳与整理临床资料归纳与整理1.突变结果讨论突变结果讨论2.临床左半左半 右半右半64.7%vs.35.3%5222433202818154405101520253035404550 Ascending colon Hepatic flexure Transverse colon Splenic flexure Descending colon Sigmoid colon RectumAmsterdam criteriaBethesda criteriaAmsterdam I&II criteriaBethesda criteriaAlln(%)15
4、(15.3%)83(84.7%)98(100%)Age(median,range)years48.1(35-67)47.6(19-82)47.7(19-82)Sex n(%)male12(80.0%)45(54.2%)57(58.2%)female3(20.0%)38(45.8%)41(41.8%)Location n(%)Ascending colon5(23.8%)20(20.4%)25(21.0%)Hepatic flexure2(9.5%)2(2.0%)4(3.4%)Transverse colon2(9.5%)8(8.2%)10(8.4%)Splenic flexure2(9.5%)
5、1(1.0%)3(2.5%)Descending colon4(19.0%)8(8.2%)12(10.1%)Sigmoid colon3(14.3%)15(15.3%)18(15.1%)Rectum3(14.3%)44(44.9%)47(39.5%)Multiple cancer synchronous tumours3(20.0%)3(3.6%)6(6.1%)metachronous tumour4(26.7%)17(20.5%)21(21.4%)Pathology adenocarcinoma13(86.7%)69(83.1%)82(83.7%)mucinous carcinoma2(13
6、.3%)11(13.2%)13(13.3%)Others0(0.0%)3(3.6%)3(3.1%)Family history155166同时异时肿瘤发生率高粘液腺癌10%31 CRC happened,11 were left side and 20 were right(64.5%vs.35.5%),20 related cancers happened,most of them were gastric cancer and endometrial carcinoma,5 each(25%).Family IDCRC numberCRC frequencyCancer numberCan
7、cer frequency MaleFemaleOnset age of CRCOnset age of cancerMultiple primary CRCMultiple primary tumorsRight siteLeft siteExtracolonic cancer(type)Mucinous carcinomaH94646314848225100H765555413737001400H86123521474711113(1St,1Es,1E)1H88113330191900102(2L)0H1664545223636112300H167465732292922151(1E)0H
8、224115723445102016(2St,2E,2Br)0H231112311474401012(1L,1Br)0H236333412404001031(1E)1H245113612565001015(2St,1Li,1L,1O)0 AC组组15例，突变例，突变4例例 如在肠外肿瘤中加入胃癌，符合如在肠外肿瘤中加入胃癌，符合30例，突例，突变变8例例 检出率相同，避免遗漏检出率相同，避免遗漏 复旦推荐标准复旦推荐标准突变Family IDMutationClinical criteriaHaving been reported(times)GeneExonNucleotideConsequ
9、enceTypeH9MSH21c.23CTp.Thr8MetMissense AmsterdamYes(5)H76MLH12c.157del GAGG Frameshift AmsterdamNoH86MLH11c.-64GTUncertainBethesdaNoH88MSH27c.1168CTp.Phe390LeuMissenseBethesdaYes(34)H166MLH18c.655AGp.Ile219ValMissense AmsterdamYes(224)H167MLH117c.1989GAAberrant splicingAmsterdamYes(2)H224MLH119c.215
10、9insGFrameshiftBethesdaNoMSH27c.1168CTp.Phe390LeuMissenseYes(34)H231MSH27c.1168CTp.Phe390LeuMissenseBethesdaYes(34)H236MLH118c.2042CTp.Ala681ValMissenseBethesdaYes(1)H245MSH27c.1168CTp.Phe390LeuMissenseBethesdaYes(34)该患者同时有两个突变，且满足复旦推荐标准 四个患者突变一致MSH2 c.1168CTInSight数据库中该位点报道结果亚洲占绝大多数潜在亚洲人种热点突变 or SN
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