家族遗传性胃癌课件

家族遗传性胃癌:基因诊断、筛查和临床处理贾淑芹北京大学肿瘤医院分子诊断中心1AutosomalDominantInheritedCancerSyndromes•BreastandOvarianCancer BRCA1&2ColonCancerand

Polyposis2HNPCCFAPPolyposisCowdensPeutz-JehgersJuvenile

PolyposisMMRAPCMYHPTENSTK11SMAD4BMPR1AOtherGI

CancersGastricPancreasMEN1MEN2/MTCVHLLi-FraumeniCDH1p16MeninRETVHLp53北京大学肿瘤医院（PKUCH)分子诊断中心(MDC)癌症遗传基因筛查101基因panel为癌症患者及其家系成员进行风险评估、遗传咨询和干预3•遗传弥漫型胃癌(HDGC)•林奇综合征(Lynch)•遗传性乳腺癌卵巢癌综合征(HBOC)•青少年息肉综合征(JPS)•黑斑息肉综合征(PJS)90%•家族性腺瘤息肉病(FAP)•李-佛美尼综合征（LFS)•……家族遗传性胃癌（-）背景5家族性胃癌的遗传风险6Chun&Ford,CancerJ.2012SyndromeGeneFrequencyGCriskHDGCCDH11-3%>56-70%LynchsyndromeMMR1/4406-13%HBOCBRCA1&21/40-1/4002.5-5%JuvenilePolyposisSMAD4,BMPR1A1/16-100,00021%Peutz-JegherSTK111/25-250,00030%FAPAPC1/10-100,0002-4%Li-FraumeniP531/50003-5%遗传性弥漫型胃癌• 1998年，首次发现于新西兰3个毛利家族中，早发的胃癌显示出常染色体显性遗传模式• 连锁分析将基因定位于16q22.1• 在3个家系中都发现E-cadherin(CDH-1）种系截短突变• 外显率：60岁前，70%的患者均患癌7遗传性弥漫型胃癌

常染色体显性遗传

早发:14~69y, 平均:37yLauren分型:

弥散型

不易早期诊断，预后差• CDH1

种系突变为特征82015版标准解读10• 2例以上胃癌，至少其中一例是弥漫型~30-40%种系突变• 年龄<40岁的弥漫型胃癌~10%种系突变• 任何一个家属同时具有弥漫型胃癌和乳腺小叶癌，其中至少一例<50岁• 个人双侧乳腺小叶癌或者多个家族成员乳腺小叶癌，一例<50岁• 患者同时具有弥漫型胃癌和唇/腭裂• 印戒细胞癌的癌前病变CDH1突变的患者印戒细胞癌中E-cadherin表达降低或缺如12• 终生患癌风险:男性携带者--67%GC女性携带者---83%GC女性携带者---60%乳腺小叶癌(LBC)• 18-40ys携带者建议行预防性全胃切除术CDH1与患癌风险(2016NCCN,V1）14HDGC中CDH1种系突变的地域差异• 低风险区（北美、加拿大、英国）---50%• 中风险区（德国）---25%• 高风险区(葡萄牙，意大利)---22%• 散发性胃癌高发区(中、日、韩)~10%15HDGC中CDH1的突变定位16临床处理遗传学检测和咨询

(E-cadherinorCDH1)• 年龄<25岁或早于先证者10年，每6-12个月做一次胃镜检查，盲取活检30块• 乳腺X光

/乳腺核磁• 预防性全胃切除vanderPost,etal.Journalofmedicalgenetics,2015.17家族遗传性胃癌（二）我们的研究18VariablesTotalNo.ofpatients(N=1603)Age,years≦3561>35and<651051≧65491SexMale1145Female458LaurenclassificationIntestinal517Diffuse864GCfamilialaggregationPositive182Negative1421HDGC(2010criteria)82HDGC(2015criteria)92Results（1）Table1.Patientinformation20c.1018A>G，p.T340A，7casesc.865G>A p.A289T，1casec.1273G>C，p.V425L，1case2.CDH1germlinemutationc.1888C>G，p.L630V，34casesc.2165-1G>A，1case211case，exon14deletion3.CDH1rearrangementinHDGCNormalE14delE14DELNormalE14del23V736MR527SL630VA289TT340AT368SV392IV425LD433G/N4. SitesofCDH1germlinemutations---------------------------------------------------------------------------------------------Missensemutation2165-1G>AE14delRearrangement---------------------------------------------------------------------------------------------Splicesitemutation246.SummaryExonSitesTypePolymorphismFunctional prediction CasesMutationrateMutationrateinHDGC inHDGCMutationReferencep.T340Amissense--benign71/82=0.0121/92=0.01106253rsnumber MAF PloyPhen SIFT(2010) (2015) rateinGC-2affect7 c.865G>Amissense - - possibly proteinp.A289T damaging1---- 1/734=0.0014 0function8 c.1018A>G deleteriou 6/1591=0.0s8 c.1103C>GTp.T368Smissensers367868307NAbenigntolerated1---- 1/734=0.00 0149c.1298A>Gp.D433Gmissensers376097289NApossiblyaffectdamagingproteinfunction1----1/734=0.00140p.V392Imissensers1418640440.0008benigntolerated1----01401406/92=0.06102119 c.1174G>A 1/734=0.0affect9 c.1273G>Cmissense - - possibly proteinp.V425L damaging1---- 1/734=0.00function11 c.1581A>Cp.R527S missense - - benign tolerated1---- 1/734=0.0 0014affect12 c.1888C>G probablyp.L630V missense rs2276331 G=0.0012 damaging protein364/82=0.04334/1568=0.functionaffect14 c.2206G>A probablyprotein 1 -- -- 1/734=0.00p.V736M missense - - damaging 14 0function14c.2165-1G>Aspliceprobablydamagingaffectproteinfunction11/82=0.141/92=0.111/734=0.0014014E14delrearrangementaffectproteinfunctionaffectproteinfunction11/82=0.141/92=0.11--026Results（2）CellfunctionstudyforCDH1L630V27aminoacid 127154708 731777882EGFRactivationExtracellulardomainJuxtamemberanedomainSrckinaseactivationP38activationL630V281.FunctionofL630VinNCI-N87cell1.1TheinfluenceofCDH1anditsmutantL630VontheproliferationinNCI-N87cellline.ODValue(490nm)00.60.70.824h48h72h96hMockWTL630V0.50.40.30.20.1Figure2CDH1hadnosignificantdifferenceontheproliferationofNCI-N87gastriccancercells,Hours300%20%40%MockWTL630V24h36h ** ** Percentageofmotilecells1.2TheinfluenceofCDH1anditsmutantL630VonthemigrationinNCI-N87cellline.Figure3CDH1mutantL630VpromotedthemigrationofNCI-N87gastriccancercellsthroughwoundhealingassay.A312.1TheinfluenceofCDH1anditsmutantL630VontheproliferationinCHOcellline.2.FunctionofL630VinCHOcellline00.80.60.40.211.21.41.624h48h72h96hMockWTL630VODValue(490nm)Figure4CDH1hadnosignificantdifferenceontheproliferationofCHOcancercells,Hours32MockWT2.2TheinfluenceofCDH1anditsmutantL630VonthemigrationinCHOcellline.0h 12h 24hFigure5CDH1mutantL630VpromotedthemigrationofCHOcancercellsthroughwoundhealingassay.Percentageofmotilecells20%L630V0%40%60%MockWTL630V80%12h24h**33DISCUSSIONCDH1anditsmutantL630Vhadnosignificantinfluenceon cancercellproliferation.CDH1mutantL630Vpromotedthemigrationofgastriccancercells.34结 论• 中国人GC中CDH1种系突变以错义突变为主，突变频率为3.14%（50/1591）• HDGC中CDH1突变频率为8.53%（or9.78%）• CDH1T340A很可能是HDGC的致病突变