医学遗传学教学课件：Cancer Genetics

CancerGeneticspreventivedoublemastectomyCancerisageneticdiseaseCancersSporadicallyoccurredHereditaryoccurredMutationsofgenesGenesmutationcausecancerencodingProteinsinsignalingpathwaysforcellproliferation.Cytoskeletalcomponentsinvolvedincontactinhibition.Regulatorsofthemitoticcycle.Componentsofprogrammedcelldeathmachinery.Proteinsresponsiblefordetectingandrepairingmutations.TypesofmutationsActivatinggain-of-functionmutationsofonealleleofaproto-oncogene.Lossoffunctionofbothalleleordominantnegativemutationofonealleleofatumor-suppressorgene.Chromosometranslocationthatcausemisexpressionofgenesorcreatechimericgenesencodingproteinsthathavegainednovelfunctionalproperties.TypesofcancersSarcomas:ariseninmesenchymaltissue:bone,muscle,orconnectivetissue;Carcinomas:originateinepithelialtissue:thecallsliningtheintestine,bronchi,ormammaryducts;Hematopoieticandlymphoidmalignancies:leukemiasandlymphomas,inbonemarrow,lymphaticsystem,andperipheralblood.FurtherclassifiedbySite,tissuetype,histologicalappearance,degreeofmalignancy.Typesofcancers Lung

Breast(women) Colon

Bladder Prostate(men)Somecommon

sarcomas: Fat Bone MuscleLymphomas: LymphnodesLeukemias: BloodstreamSomecommoncarcinomas:肿瘤的几大生物学特征不受控生长，局部占位，损坏器官功能转移游走，多处占位，损坏多器官功能物理和化学效应，个体全面衰竭肿瘤研究内容病因学研究（环境致癌因素的筛查）遗传学研究（单基因遗传性肿瘤、多基因遗传性易感）癌细胞的“还原性”研究（癌基因、癌蛋白的发现及功能研究）新的诊断治疗方法的发明（化学、药物、免疫、靶向药、技术、设备、材料）治疗效果的临床验证关于病因及机理我们知道什么80%是环境因素遗传因素分为三个层面单基因遗传多基因易感，处于研究阶段是唯一的体细胞基因突变的疾病

机体免疫状态与肿瘤发生有关WhatCausesCancer?SomevirusesorbacteriaHeredityDietHormonesRadiationSomechemicalsPopulation-BasedStudiesCANADA:LeukemiaRegionsofHighestIncidenceBRAZIL:CervicalcancerU.S.:

ColoncancerAUSTRALIA:SkincancerCHINA:LivercancerU.K.:LungcancerJAPAN:StomachcancerHeredity?Behaviors?OtherFactors?1005050StomachCancer(Numberofnewcases

per100,000people)U.S.JapanJapanesefamilies

inU.S.1007070ColonCancer

(Numberofnewcases

per100,000people)U.S.JapanJapanesefamilies

inU.S.ThreePatternsofTumorInheritanceHeredityfamilialtumorsyndrome(monogenicinheritance)Multigeniccancergeneticsusceptibility(multigeneinvolved)Somatictumorcellgenerearrangement(acquired)HereditaryFamilialTumorSyndrome

GermlinegenedefectSomaticcell,especiallygermcellsVerticalinheritancetodescendentsMostlyautosomaldominantinheritanceClinicalcharacteristics(syndrome)Morethan20hereditaryfamilialtumorgeneclonedStudystrategy–linkageanalysis,positionalcloningAccountfortotaltumormorbidity≤1%CriteriaofHFTSidentification

1.Ageofindividualonset2.Familyaggregation3.Clinicalsyndrome4.Gene’sdiagnosisExamplesofHFTSinvolvedGenes

Transcriptionalregulatoryfactor(regulatecellcycle)Rb、WTI、P53DNArepairenzymegenesERCC、FACCDNAligasehmsH1、hmsH2CytoskeletonandcelladhesiongenesAPC、medlin综合征肿瘤相关特征/CA染色体定位克隆基因作用机理家族性视网膜母细胞瘤视网膜母细胞瘤骨肉瘤发育迟缓13q14RbRetinoblastoma调节细胞周期结合病毒癌基因转录调控E2F家族性Wilms肿瘤Wilms肿瘤WAGRWilms肿瘤无虹膜泌尿生殖系统异常智力发育迟缓Deny-DrashBeckwith-Wiedemann综合征Organomegaly肾上腺皮质癌肝母细胞癌11q13

11p15WT1锌指转录因子调节细胞周期多发性内分泌瘤2型（Sipple综合征）

髓样甲状腺癌甲状旁腺增生前垂体腺瘤2型A

嗜铬细胞瘤甲状旁腺增生2型B

嗜铬细胞瘤粘膜神经瘤

Marfanoidhabitus

家族性髓样甲状腺癌10cen-10q11.2

Ret

受体酪氨酸激酶着色性干皮病皮肤癌着色异常

性腺机能减退

CNS缺陷8个互补群ERCCXPA-XPG螺旋酶核酸外切修复Franconi贫血AML各种血细胞减少骨髓异常4个互补群FACCDNA修复46BR淋巴网状内皮增生症阳光过敏免疫缺陷生长迟缓DNA连接酶1DNA连接家族性肿瘤综合征

译自AbeloffMD,etal.ClinicalOncology.NewYork:CurchillLivingsto,1995.168家族性肿瘤综合征综合征肿瘤相关特征/CA染色体定位克隆基因作用机理Bloom综合征实体瘤毛细血管扩张免疫损伤BloomDNAHelicase毛细血管扩张共济失调AtaxiaTelangiectasia

淋巴瘤小脑共济失调毛细血管扩张免疫缺陷5个互补群11q22-q23ATMDNArepair家族性腺瘤息肉病结肠癌结肠息肉先天性视网膜色素上皮肥大Gardner综合征5q21APC结合cateninHNPCC（Lynch综合征）结肠癌结肠癌HNPCCI型HNPCCII型子宫内膜癌（其他）3p212p16hMLH1hMSH2DNA错配修复DNA错配修复Li-Fraumeni综合征肉瘤乳腺癌肾上腺皮质癌脑瘤17qp53调节细胞周期及其他转录因子防UV损伤神经纤维瘤病1型（NF1）（von-Reckling-hausen病）神经纤维瘤

神经纤维肉瘤Café-au-lait斑

Lisch小结视神经胶质瘤17q11.2NF1GAP相关的p21-ras调控与微管有关神经纤维瘤病2型听神经瘤脑膜瘤Schwann细胞瘤视神经胶质瘤22q12Merlin连接细胞膜和细胞骨架家族性乳腺癌乳腺癌乳腺癌卵巢癌17q21.113q12-13BRCAI

BRCA2

转录因子

译自AbeloffMD,etal.ClinicalOncology.NewYork:CurchillLivingsto,1995.168GeneticSusceptibilityofCancers(1)

ConceptionofsusceptibilityCharacteristics:a.Environmentaldependentb.Multigeneinvolvedc.Geneticchangeisslight,bothstructurallyandfunctionally(i.e.SNP)d.Slightlypronetofamilialaggregation、

highincidentpopulationGeneticSusceptibilityofCancers(2)EnvironmentHeredityGeneticSusceptibilityofCancers(3)FeaturesofEnvironmentalCarcinogenThreetypesenvironmentcarcinogenachemicalbphysicalcbiologicalCommonfeaturesanonfatalinjurybtime、bodysite、way、duration、doseofexposurecstronglyrelyonindividualsusceptibility(metabolism、compensation、repair、immunity)GeneticSusceptibilityofCancers(4)

1.SNP(SingleNucleotidePolymorphism)∝pointmutation2.Distributionfrequencyinhumangenome1%,~1/1000bp3.SomeSNPsarerelatedtodiseasesusceptibilitySitesofSNPsintronexonpromoteraachangenoaachangeFormsofSNP’sinfluenceonfunctionInfluenceonresponsibleexpression(responsetospecialenvironment)Influenceonsecondarystructurealteration(proteinbinding,antigenpresentation)Influenceongeneactivity(dominancerecessive,genedosageeffect)Isogeneticcombinedeffect(fatal)Influenceonshearing(intronboundary)GeneticSusceptibilityofCancers(5)

GeneralStrategyofStudyHastobeknowngeneCandidategeneselectionScientificdesignoftheexperimentMaintechnologies:PCR-SSCP,DHPLC,sequencingetal

FunctionalrelevanceconfirmationGeneticSusceptibilityofCancers(6)

CategoryofcandidategenesChemicalmetabolicenzymessystemDNAdamage-repairsystemImmunologicalrecognition-regulation-reactionsystemBiologicalfactorsvscellularinteractionfactorsApoptosisgenesGeneticSusceptibilityofCancers(7)

ProceduresofdefiningSusceptibleGeneCandidatesselectionSNPdiscoveryandanalysisTestingfrequencyofspecificSNPinhigh-riskgroupComparisonofSNPfrequenciesbetweendiseasegroupandcontrolInteractionanalysisofSNPs,haplotypeconstructionFunctionaltestGeneticSusceptibilityofCancers(8)

SignificanceofdefiningSusceptibleGeneHigh-riskpopulationidentifyingInterventionandpreventionofcancersEarlydiagnosisandtreatmentMolecularmechanismsofcarcinogenesisOncogenesandTumorSuppressorGenes

inTumorCellFeaturesofOncogenesandTumorSuppressorGenes

Genesinchargeofproliferation、

differentiation、apoptosisOncogeneAmutantgenealteredfunctionorexpressionabnormalstimulationofcelldivisionandproliferation.Theactivatingmutationcanbe:itself;regulatoryelements;orgenomiccopynumberunregulatedfunctionoroverexpressionoftheoncogene.Dominanteffect.OncogenesMutated/damagedoncogeneOncogenesacceleratecellgrowthanddivisionCancercellNormalcellNormalgenesregulatecellgrowthProto-OncogenesandNormalCellGrowthReceptorNormalGrowth-ControlPathwayDNACellproliferationCellnucleusTranscription

factorsSignalingenzymesGrowthfactorOncogenesareMutantFormsofProto-OncogenesCellproliferationdrivenbyinternaloncogenesignalingTranscriptionActivatedgeneregulatoryproteinInactiveintracellularsignalingproteinSignalingproteinfromactiveoncogeneInactivegrowthfactorreceptorTumorSuppressorGenesNormalgenespreventcancerRemoveorinactivatetumorsuppressorgenesMutated/inactivatedtumorsuppressorgenesDamagetobothgenesleadstocancerCancercellNormalcellTumorSuppressorGenesActLikeaBrakePedalTumorSuppressorGeneProteinsDNACellnucleusSignalingenzymesGrowthfactorReceptorTranscription

factorsCellproliferationTumorsuppressorGate-keepers:directlyinvolvedinregulationofthecellcycleorgrowthinhibition.eg,p53.Caretakers:involvedinrepairingDNAdamageandmaintaininggenomicintegrity,eg,WRN.TheStructureofp531393IIIIIIIVVTransactivationDomainDNABindingDomainTetramerizationDomainNLSINLSIINLSIIINC*DNA-BindingRegulatoryRegionTumorsuppression•Transcriptionalactivatorandrepressor•Mutationsinalmosteverykindoftumors•StressResponseofp53StressDNAdamagep53ActivateTargetsCellgrowtharrestApoptosisSenescenceActivationPhosphorylation

AcetylationStabilizationMajorPost-translationalModificationofp53Mdm2p531.Ubiquitination2.Phosphorylation3.Acetylationp53Pp53AATM/ATRCBP/p300Mdm2DNADamageMDM2APPhosphorylationAcetylationp53CBP/p300PCAFTFsTFsTFsp53p53PCAFTFsCBP/p300RNAPolymeraseIIAAAAPPMDM2p53GrowthArrestCellularSenescenceApoptosisWRNisamemberofRecQfamilyWRNphysicallyandfunctionallyinteractswithmanyproteinsWRN

TelomeremaintenanceTRF1TRF2POT1

DNAreplicationpolδRPAPCNAFEN1TopoI

DNADSBrepairHRNHEJp53MRNRad51Rad52BLMBRCA1Ku70/Ku80DNA-PKcsX4L4

DNABERpolβPPAR-1WernersyndromeAutosomalrecessivedisorders.Werner'ssyndromeisnamedafterOttoWerner,aGermanscientist,describedthesyndromeaspartofhisdoctoralthesisin1904.Wernersyndromepatientstypicallydevelopnormallyuntiltheyreachpuberty.Followingpubertytheyagerapidly,byage40theyoftenappearseveraldecadesolder.Numerousfeaturesofprematureageing:grayingandlossofhair,wrinklingandulcerationofskin,atherosclerosis,osteoporosis,andcataracts.Shortstatureduetolackofusualgrowthspurtduringpuberty.

PredispositionforcancerMostlyassociatedwithsofttissuesarcomas,osteosarcoma.WernersyndromepatientWilliamandWilkensPublishingInc.Chromosometranslocationcausemisexpressionofgenesorcreatechimericgenesencodingproteinsthathavegainednovelfunctionalproperties.Philadelphiachromosometranslocation,t(9;22)(q34;q11).FormBCR-ABLcausesChronicmyelogenousleukemia(CML).ImatinibtreatCMLbyinhibitingtyrosinekinaseactivity.Ph1translocation:t(9;22)(q34;q11)CancerPreventionCancervirusesorbacteriaCarcinogenicradiationCarcinogenicchemicalsAvoidTobacco15x