肿瘤遗传标记-DNA修复与肿瘤发病风险的研究-NoSl.ppt

,肿瘤遗传标记-DNA修复与肿瘤发病风险的研究,M.D.,Ph.D.流行病系,美国休斯顿德州医学中心MDAndersonCancerCenter,肿瘤死亡病因,电离辐射3%,Tobacco30%,酗酒5%,成年人膳食和肥胖症30%,其他7%,免疫因素5%,缺乏运动5%,遗传因素5%,病毒感染5%,产前因素和生长因素5%,HarvardSchoolofPublicHealth,1998,基本数据:百万美国人口:300.0吸烟者:46.5每年癌症患者1.3每年肺癌患者0.5每年头颈部癌患者0.04,吸烟与肿瘤,ACS,2009,遗传因素一定在起作用!,PetoJ,Nature,2001,吸烟在不同人群中有不同危害,中国,美国,DNA损伤-修复与肿瘤发生的机制,p53ProteinAccumulation,ModifiedfromHarris,1994,DNA修复基因和肿瘤发生,基因肿瘤,XP(A)皮肤癌XP(B)皮肤癌XP(C)皮肤癌XP(D)皮肤癌XP(E-G)皮肤癌hMLH1结肠癌hPSM1/2结肠癌hMSH2结肠癌hMSH3结肠癌hMSH6结肠癌pRB视网膜母细胞瘤P53,hCHK2Li-Fraumeni综合症P16黑色素瘤ATM乳腺癌BRCA1/2乳腺癌,正常修复功能,修复功能缺陷,DNA修复的特定通路,人类DNA修复通路,修复类型基因种类损伤种类,单碱基剪切修复DNAligase(LIG3),单碱基损伤DNAglycosylase(MBD4,MPG,MYH,NTH1,OGG1,SMUG1,TDG,UNG),APE1,APE2,XRCC1,ADPRT,ADPRTL2,ADPRTL3.,多碱基剪切修复XPA,XPC,XPE,XPF/ERCC4,多碱基损伤XPG/ERCC5,ERCC1,LIG1,（紫外线、吸烟）CSB/ERCC6,CSA/CKN1,XAB2,TFIIH(XPB/ERCC3XPD/ERCC2,GTF2H1,GTF2H21,GTF2H3,GTF2H4,CDK7,CCNH,MNAT),DDB1,DDB2,MMS19,CENN2,AD23A,RAD23B,RPA1,RPA2,RPA3.,碱基错配修复MSH2,MHS3,MSH6,MSH4,碱基错配MSH5,MLH1,MLH3,PMS1,PMS2,PMS2L3,PMS2L4.,Woodetal,Science,2001,重组修复RAD50,RAD51,RAD51B,RAD51C,DNA双链断裂RAD51D,RAD54L,RAD54B,V(D)J重组RAD52,DMC1,MRE11A,NBS1,ERCC1,XPF/ERCC4,XRCC2XRCC3,XRCC4,XRCC5,XRCC6XRCC7,XRCC8,BRCA1,BRCA2.,XP病人和正常人中皮肤癌发生的年龄分布,Kraemer,PNAS,1997,Skincancersinnormalpopulation,SkincancersinXPpopulation,XP=xerodermapigmentosum,变量病例对照OR(95%CI)PvalueNo.(%)No.(%)总数895898年龄0.49355439(49.1)455(50.7)55456(50.9)443(49.3)性别0.231男674(75.3)654(72.8)女221(24.7)244(27.2)种族0.859白人767(85.7)763(85.0)西裔69(7.7)70(7.8)非裔59(6.6)65(7.2)吸烟0.0001从无291(32.5)310(34.5)1.39(1.091.78)曾经239(26.7)441(49.1)1.00未间断365(40.8)147(16.4)3.97(3.085.13)喝酒0.0001从无235(26.3)398(44.3)1.00曾经206(23.0)149(16.6)2.12(1.602.81)未间断454(50.7)351(39.1)2.10(1.682.63)家族史0.748有516(57.7)511(56.9)1.00无379(42.3)387(43.1)1.01(0.83-1.23),头颈部肿瘤病例-对照研究中部分变量的频数分布2000-2006,*Differencesbetweencasesandcontrolswereanalyzedbytwo-sided2andStudentsttests,实验室血样处理流程,烟草致癌物诱导的DNA损伤与修复机制,NERCoreProteins,ERCC1XPAXPB/ERCC3XPCXPD/ERCC2XPE/DDB1/2XPE/ERCC4XPG/ERCC5,Neumannetal.,MolCarcino,2005,Lietal.,IntJCancer.2001,BPDE-诱导DNA加成物的检测,头颈部肿瘤研究,CancerRes2007;67:(12).June15,2007,变量病例(n=803)对照(n=839)PorOR(95%CI)*n(%)n(%)总数加成物中位数29.22/107508(63.3)419(50.0)1.71(1.392.10)白人加成物中位数29.22/107431(64.7)338(51.2)1.81(1.452.27)*Adjustedforthematchingvariables:age(inyears),sex,ethnicity,smokingandalcoholuse.,染色体对DNA损伤剂的敏感性测定,变量病例(n=895)对照(n=898)PorOR(95%CI)*n(%)n(%)总数中位数0.43548(61.2)457(50.9)1.57(1.291.90)白人中位数0.43465(60.6)381(49.9)1.56(1.271.91)*Adjustedforthematchingvariables:age(inyears),sex,ethnicity,smokingandalcoholuse.,CancerRes2008;68:(11).June1,2008,宿主报告基因的DNA损伤修复测定,BPDE,BPDE,Qiaoetal.,MutatRes,2002,调整相对比数,DRC(%)四分位数,个体DNA修复功能与头颈部肿瘤发病分险,HighLow,Lietal.,CanRes,2007,病例=721对照=721,趋势检验:P0.0001,修复功能,Cases=767Controls=763,趋势检验:P=0.0001,染色体敏感性,DNA加成物,Wangetal.,CCR,2009,Wangetal.,CancerRes,2007,反式蛋白质芯片测定修复蛋白水平,Weietal.,CEBP,2005,57病例，63对照,0.01.02.03.04.05.06.07.0相对比数,相对表达水平:ERCC1XPAXPCXPD/ERCC2XPF/ERCC4XPG/ERCC5(comparedtobeta-actin),NER修复蛋白水平与头颈部肿瘤发病风险,病例=57对照=63,Weietal.,CEBP,2005,Genersno.Allele1Allele2CodonWtVariantVarfreERCC1NoneERCC21799793GA312ASP(D)ASN(N)0.241052559AC751LYS(K)GLN(Q)0.22ERCC3NoneERCC42020955TC662SER(S)PRO(P)0.06ERCC517655GC1104ASP(D)HIS(H)0.38ERCC62228528GA399GLY(G)ASP(D)0.222228526AG1097MET(M)VAL(V)0.182228527AG1213ARG(R)GLY(G)0.194253211GC1230ARG(R)PRO(P)0.082228529AG1413GLN(Q)ARG(R)0.19XPANoneXPC2228000CT499ALA(A)VAL(V)0.242228001AC939LYS(K)GLN(Q)0.34,多碱基剪切修复基因多态位点及对其功能的影响,(nsSNPsinNERgenes),多碱基剪切修复基因多态位点与头颈部肿瘤发病风险,NER-SNPs829/854OR(95%CI)ERCC1C8092AAAvsCC+CA0.9(0.6-1.4)XPAG23AAAvsGG+AG0.9(0.7-1.2)XPCAla499ValVal/ValvsAla/Ala+Ala/Val1.7(1.2-2.4)Lys939GlnGln/GlnvsLys/Lys+Lys/Gln1.1(0.8-1.4)ERCC2/XPDAsp312AsnAsn/AsnvsAsp/Asp+Asp/Asn1.2(0.9-1.7)Lys751GlnGln/GlnvsLys/Lys+Gln/Gln1.1(0.8-1.4)XPG/ERCC5His1104AspAsp/AspvsHis/His+His/Asp0.8(0.5-1.3)AllSNPscombinedasNo.ofvarianthomozygotesno.(%)no.(%)OR(95%CI)0-2114(13.8)140(16.3)1.03453(54.6)477(55.9)1.2(0.9-1.6)4194(23.4)177(20.7)1.4(1.0-1.9)553(6.4)55(6.4)1.2(0.8-2.0)615(1.8)5(0.6)4.1(1.4-12.0)Pfortrend0.017,GeneComparisonCases/ControlsRisk*,*Adjustedforage,sex,smokingandalcoholuse(Anetal.,CEBP,2007),结论,需要有高通量基因型检测的平台，乃至个体全基因遗传变异的测定和建立多元回归预警数学模型,个体DNA修复功能低下增加头颈部肿瘤的发病风险,