醫(yī)學(xué)遺傳學(xué)教學(xué)課件：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:腫瘤的幾大生物學(xué)特征不受控生長(zhǎng)，局部占位，損壞器官功能轉(zhuǎn)移游走，多處占位，損壞多器官功能物理和化學(xué)效應(yīng)，個(gè)體全面衰竭腫瘤研究?jī)?nèi)容病因?qū)W研究（環(huán)境致癌因素的篩查）遺傳學(xué)研究（單基因遺傳性腫瘤、多基因遺傳性易感）癌細(xì)胞的“還原性”研究（癌基因、癌蛋白的發(fā)現(xiàn)及功能研究）新的診斷治療方法的發(fā)明（化學(xué)、藥物、免疫、靶向藥、技術(shù)、設(shè)備、材料）治療效果的臨床驗(yàn)證關(guān)于病因及機(jī)理我們知道什么80%是環(huán)境因素遺傳因素分為三個(gè)層面單基因遺傳多基因易感，處于研究階段是唯一的體細(xì)胞基因突變的疾病

機(jī)體免疫狀態(tài)與腫瘤發(fā)生有關(guān)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綜合征腫瘤相關(guān)特征/CA染色體定位克隆基因作用機(jī)理家族性視網(wǎng)膜母細(xì)胞瘤視網(wǎng)膜母細(xì)胞瘤骨肉瘤發(fā)育遲緩13q14RbRetinoblastoma調(diào)節(jié)細(xì)胞周期結(jié)合病毒癌基因轉(zhuǎn)錄調(diào)控E2F家族性Wilms腫瘤Wilms腫瘤WAGRWilms腫瘤無虹膜泌尿生殖系統(tǒng)異常智力發(fā)育遲緩Deny-DrashBeckwith-Wiedemann綜合征Organomegaly腎上腺皮質(zhì)癌肝母細(xì)胞癌11q13

11p15WT1鋅指轉(zhuǎn)錄因子調(diào)節(jié)細(xì)胞周期多發(fā)性內(nèi)分泌瘤2型（Sipple綜合征）

髓樣甲狀腺癌甲狀旁腺增生前垂體腺瘤2型A

嗜鉻細(xì)胞瘤甲狀旁腺增生2型B

嗜鉻細(xì)胞瘤粘膜神經(jīng)瘤

Marfanoidhabitus

家族性髓樣甲狀腺癌10cen-10q11.2

Ret

受體酪氨酸激酶著色性干皮病皮膚癌著色異常

性腺機(jī)能減退

CNS缺陷8個(gè)互補(bǔ)群ERCCXPA-XPG螺旋酶核酸外切修復(fù)Franconi貧血AML各種血細(xì)胞減少骨髓異常4個(gè)互補(bǔ)群FACCDNA修復(fù)46BR淋巴網(wǎng)狀內(nèi)皮增生癥陽光過敏免疫缺陷生長(zhǎng)遲緩DNA連接酶1DNA連接家族性腫瘤綜合征

譯自AbeloffMD,etal.ClinicalOncology.NewYork:CurchillLivingsto,1995.168家族性腫瘤綜合征綜合征腫瘤相關(guān)特征/CA染色體定位克隆基因作用機(jī)理Bloom綜合征實(shí)體瘤毛細(xì)血管擴(kuò)張免疫損傷BloomDNAHelicase毛細(xì)血管擴(kuò)張共濟(jì)失調(diào)AtaxiaTelangiectasia

淋巴瘤小腦共濟(jì)失調(diào)毛細(xì)血管擴(kuò)張免疫缺陷5個(gè)互補(bǔ)群11q22-q23ATMDNArepair家族性腺瘤息肉病結(jié)腸癌結(jié)腸息肉先天性視網(wǎng)膜色素上皮肥大Gardner綜合征5q21APC結(jié)合cateninHNPCC（Lynch綜合征）結(jié)腸癌結(jié)腸癌HNPCCI型HNPCCII型子宮內(nèi)膜癌（其他）3p212p16hMLH1hMSH2DNA錯(cuò)配修復(fù)DNA錯(cuò)配修復(fù)Li-Fraumeni綜合征肉瘤乳腺癌腎上腺皮質(zhì)癌腦瘤17qp53調(diào)節(jié)細(xì)胞周期及其他轉(zhuǎn)錄因子防UV損傷神經(jīng)纖維瘤病1型（NF1）（von-Reckling-hausen?。┥窠?jīng)纖維瘤

神經(jīng)纖維肉瘤Café-au-lait斑

Lisch小結(jié)視神經(jīng)膠質(zhì)瘤17q11.2NF1GAP相關(guān)的p21-ras調(diào)控與微管有關(guān)神經(jīng)纖維瘤病2型聽神經(jīng)瘤腦膜瘤Schwann細(xì)胞瘤視神經(jīng)膠質(zhì)瘤22q12Merlin連接細(xì)胞膜和細(xì)胞骨架家族性乳腺癌乳腺癌乳腺癌卵巢癌17q21.113q12-13BRCAI

BRCA2

轉(zhuǎn)錄因子

譯自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