家族遗传性胃癌 课件.pptx

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1、,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1,Autosomal Dominant Inherited Cancer SyndromesBreast and Ovarian CancerBRCA1&2Colon Cancer and Polyposis,2,HNPCCFAPPolyposisCowdensPeutz-JehgersJuvenile Polyposis,MMR APC MYH PTEN STK11 SMAD4 BMPR1A,Other GI Cancers,GastricPancreasMEN1MEN2/MTCVHLLi-Fraumeni,

2、CDH1p16 Menin RET VHLp53,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,癌症的遗传易感性,4,谁应该做癌症遗传易感性检测？,若携带与癌症相关的已知基因突变，患癌的风险有多大？,对于未发病的携带者，我们能做些什么？,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,6,Chun

3、&Ford,Cancer J.2012,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:1469y,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,8,HDGC 诊断标准（IGCLC),2.3 confirmed DGC cases in 1st or 2nd degree relatives independent of ag

4、e,Single DGC40Personal or family history of DGC and LBC,1 case50,Single DGC40Personal or family history of DGC and LBC,1 case50,20101.2 GC cases in family,one confirmed DGC50,20151.2 GC cases in family,one confirmed DGC,19991.2 GC cases in family,one confirmed DGC50,2.3 confirmed DGC cases in 1st or

5、 2nd degree relatives independent of age,9,2015 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,11,CDH1 突变的患者印戒细胞癌中E-cadherin表达降低或缺如,12,CDH1 与患癌风险,终生患癌风险:男性携带者-70%GC女性携带者-56%GC女性携带者-42%乳腺小叶癌(LBC)中位发病年龄 毛利族:

6、32 yrs其他：43 yrs,13,Hansford&Huntsman,JAMA Onc 2015,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,14,CDH1 与患癌风险(2016 NCCN,V1）,HDGC中CDH1种系突变的地域差异,15,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%,HDGC中CDH1的突变定位,16,临床处理,遗传学检测和咨询(E-cadherin or CDH1)年龄25岁或早于先证

7、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,van der Post,et al.Journal of medicalgenetics,2015.,17,家族遗传性胃癌（二）我们的研究,18,Material and Methods,19,Samples:103 HDGC1500 sporadic GC3097 normal controlMethods:16 exons PCR+sequencingGC：site sequencingFamilies and controls：MLPAHDGC,20,Results（1）Table 1.Patien

8、t information,c.1018AG，p.T340A，7 cases,c.865GAp.A289T，1 case,c.1273GC，p.V425L，1 case,2.CDH1 germline mutation,c.1888CG，p.L630V，34 cases,c.2165-1 GA，1 case,21,c.1298AG,p.D433G,1 case,c.2206GA,p.V736M，1 case,c.1103CGT,p.T368S，1 case,c.1174GA,p.V392I，1 case,c.1581AC,p.R527S，1 case,22,1 case，exon14 dele

9、tion,3.CDH1 rearrangement in HDGC,Normal,E14del,E14DEL,Normal,23,E14del,V736M,R527S,L630V,A289TT340A T368S V392I V425LD433G/N,4.Sites of CDH1 germline mutations,-Missense mutation,2165-1 GA,E14del,Rearrangement-Splice site mutation,24,5.CDH1 L630V and GC,25,CDH1 L630V mutation in GC andnormal contro

10、ls,6.Summary,Exon,Sites,Type,Polymorphism,Functional,prediction,Cases,Mutation rate Mutation ratein HDGCin HDGC,Mutation,Reference,p.T340A,missense,-,-,benign,7,1/82=0.012,1/92=0.011,0625,3,9,c.1298AGp.D433G,missense,rs376097289,NA,possibly,affect,damaging protein,function,1,-,-,1/734=0.0014,0,p.V39

11、2I,missense,rs141864044,0.0008,benign,tolerated,1,-,-,014,0,14,0,6/92=0.061,021,1,14,c.2165-1 GA,splice,probably damaging,affect protein function,1,1/82=0.14,1/92=0.11,1/734=0.0014,0,14,E14del,rearrange ment,affect protein function,affect protein function,1,1/82=0.14,1/92=0.11,-,0,26,Results（2）Cell

12、function study for CDH1 L630V,27,amino acid1,27,154,708731 777,882,EGFR activation,Extracellular domain,Juxtamemberane domain,Src kinase activation,P38 activation,L630V,28,B,Figure 1 Confirmation of wild-type or mutant CDH1(L630V)FLAG fusion protein expressing in gastric cancer cell line and CHO cel

13、l line(A NCI-N87 cell line B CHO cell line).,A,FLAG,-actin,(NCI-N87 cell line),FLAG,-actin,(CHO cell line),29,1.Function of L630V in NCI-N87 cell,1.1 The influence of CDH1 and its mutant L630V on the proliferation in NCI-N87 cell line.,OD Value(490nm),0,0.6,0.7,0.8,24h,48h,72h,96h,Mock WT,L630V0.50.

14、40.30.20.1,30,Figure 2 CDH1 had no significant difference on the proliferation of NCI-N87 gastric cancer cells,Hours,0%,20%,40%,Mock,WT,L630V,24h 36h,*,*,31,Percentage of motile cells,1.2 The influence of CDH1 and its mutant L630V on the migration in NCI-N87 cell line.,Figure 3 CDH1mutant L630V prom

15、oted the migration of NCI-N87 gastric cancer cells through wound healing assay.,A,2.1 The influence of CDH1 and its mutant L630V on the proliferation in CHO cell line.,2.Function of L630V in CHO cell line,0,0.80.60.40.2,1,1.2,1.4,1.6,24h,48h,72h,96h,Mock WT L630V,32,OD Value(490nm),Figure 4 CDH1 had

16、 no significant difference on the proliferation of CHO cancer cells,Hours,Mock,WT,2.2 The influence of CDH1 and its mutant L630V on the migration in CHO cell line.0h12h24h,Figure 5 CDH1mutant L630V promoted the migration of CHO cancer cells throughwound healing assay.,Percentage of motile cells,20%L

17、630V0%,40%,60%,Mock,WT,L630V,80%12h,24h,*,33,DISCUSSIONCDH1 and its mutant L630V had no significantinfluence oncancer cell proliferation.CDH1mutant L630V promoted the migration ofgastric cancer cells.,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%（or 9.78%）CDH1 T340A很可能是HDGC的致病突变

18、CDH1L630V在我国正常人群和GC、HDGC人群中突 变频率均无显著差异,35,结论,36,90%以上的HDGC 无CDH1种系突变，CDH1种,系突变可能不是我国HDGC的主要遗传易感基因。本研究为国内家族遗传性胃癌的预防性切除术积累数据，提供理论及实践的基础。,家族遗传性胃癌（三）案例分析,37,35号家系 CDH1 T340A,:carrier:gastric cancer Lung cancer Esophegeal cancer Breast cancer TestedCancerSomatic mutation T340A,61y,38,34y,40y,35号家属，34y，男性，CDH1 T340A,39,688号家系 CDH1 L630V,40,GC:gastric cancer IGC:intestinal GCEndC:endometrial cancer,688-2,41,688-4,42,688-8,43,688-9,44,688-14,45,建 议 流 程,46,详细地家系咨询，患者知情同意，遗传学检测家系随访“肿瘤易感基因panel”检测及复检通知18-40y，无症状致病突变携带者在遗传门诊咨询建议进行胃镜检测及取24-30块活检、病检根据结果进一步遗传门诊治疗或随访建议,47,