医学遗传学16肿瘤遗传学.ppt

16遗传与肿瘤发生CancerGenetics,TheancientGreeksbelievedthatcancerwascausedbytoomuchbodyfluidtheycalledblackbile.,Doctorsintheseventeenthandeighteenthcenturiessuggestedthatparasitescausedcancer.Today,doctorsunderstandmoreaboutthelinkbetweencancerandgenetics.,Viruses,ultraviolet(UV)radiation,andchemicalscanalldamagegenesinthehumanbody.Ifparticulargenesareaffected,apersoncandevelopcancer.Understandinghowgenescausecancer,though,firstrequiresabasicunderstandingofseveralgenetictermsandconcepts.,1.General,Cancerisaverycommondisease,affectingabout1in3individuals,andabouthalfthepeoplethatcontractcancerwilldieasadirectresultoftheirdisease.,Forthemostpart,cancerarisesfromasinglecell,thatis,cancerisaclonaldisease.Theaveragehumanbeingcontainsabout1014cells(i.e.,100,000,000,000,000cells),anyoneofwhichcould,inprinciple,becomeacancercell,ifitacquiredtherightsortofmutationswhileitstillhadthepotentialtoproliferate.,Therefore,thecancercellarisesandprogressesonceoutofapossible1014cellulartargets.Thatonlyhappensin1in3people.Eventhenitusuallytakes60or70yearstooccur.,TumorsarehereditaryHereditaryretinoblastomaisanautosomaldominanttraitinwhichsusceptibilitytoretinoblastomaisinherited.ThisisanunusualdominanttraitinthatamutationinoneRBgeneisnotsufficienttocausesymptoms,butmutationsinthesecondalleleoftenariseduringdevelopment.,Offspringhavea50%chanceofreceivingthemutantgenefromaheterozygousparent,and90%ofcarrierswilldevelopretinoblastoma,usuallyinbotheyes.Thehereditaryformisalsoassociatedwithahighriskforothercancersespeciallyoftheboneandfibroustissues(osteosarcomasandfibrosarcoma.,Sporadicretinoblastomaisatraitinwhichtheaffectedindividualhasnotinheritedanymutantallelesoftheretinoblastomagene.,Themutationsoccurafterbirthandresultintumorformation.Tumorsusuallydevelopinonlyoneeyeandpatientsarenotathighriskforothercancers.Bothallelesneedtobemutatedinasinglecell,andthatiswhythisformtypicallyoccursonlyinoneeye.,ChromosomeandtumorsDetailedstudiesofthePhiladelphiachromosomeshowthatmostofchromosome22hasbeentranslocatedontothelongarmofchromosome9.Inaddition,thesmalldistalportionoftheshortarmofchromosome9istranslocatedtochromosome22.Thistranslocation,whichisfoundonlyintumorcells,indicatesthatapatienthaschronicmyelogenousleukemia(CML).InCML,thecellsthatproducebloodcellsforthebody(thehematopoieticcells)growuncontrollably,leadingtocancer.,TheconnectionbetweenthischromosomalabnormalityandCMLwasclarifiedbystudyingthegeneslocatedonthechromosomesatthesitesofthetranslocationbreakpoints.,Inoneofthetranslocatedchromosomes,partofagenecalledablismovedfromitsnormallocationonchromosome9toanewlocationonchromosome22.Thisbreakageandreattachmentleadstoanalteredablgene.Theproteinproducedfromthemutantablgenefunctionsimproperly,leadingtoCML.,2.oncogene,Oncogenesaremutatedformsofgenesthatcausenormalcellstogrowoutofcontrolandbecomecancercells.Theyaremutationsofcertainnormalgenesofthecellcalledproto-oncogenes.,Proto-oncogenesarethegenesthatnormallycontrolhowoftenacelldividesandthedegreetowhichitdifferentiates(orspecializes).Whenaproto-oncogenemutates(changes)intoanoncogene,itbecomespermanentlyturnedonoractivatedwhenitisnotsupposedtobe.Whenthisoccurs,thecelldividestooquickly,whichcanleadtocancer.,Itmaybehelpfultothinkofacellasacar.Forittoworkproperly,thereneedtobewaystocontrolhowfastitgoes.Aproto-oncogenenormallyfunctionsinawaythatissimilartoagaspedal-ithelpsthecellgrowanddivide.Anoncogenecouldbecomparedtoagaspedalthatisstuckdown,whichcausesthecelltodivideoutofcontrol.,Thepathwayfornormalcellgrowthstartswithgrowthfactor,whichlocksontoagrowthfactorreceptor.Thesignalfromthereceptorissentthroughasignaltransducer.Atranscriptionfactorisproduced,whichcausesthecelltobegindividing.Ifanyabnormalityisdetected,thecellismadetocommitsuicidebyaprogrammedcelldeathregulator.,Morethan100oncogenesarenowrecognized,andundoubtedlymorewillbediscoveredinthefuture.Scientistshavedividedoncogenesintothe5differentclasses.,GrowthfactorsTheseoncogenesproducefactorsthatstimulatecellstogrow.Thebestknownoftheseiscalledsis.Itleadstotheoverproductionofaproteincalledplatelet-derivedgrowthfactor,whichstimulatescellstogrow.,GrowthfactorreceptorsThesearenormallyturnedonoroffbygrowthfactors.Whentheyareon,theystimulatethecelltogrow.Certainmutationsinthegenesthatproducethesecausethemtoalwaysbeon.Inothercases,thegenesareamplified.,Thismeansthatinsteadoftheusual2copiesofthegene,theremaybeseveralextras,resultingintoomanygrowthfactorreceptormolecules.Asaresult,thecellsbecomeoverlysensitivetogrowth-promotingsignals.,ThebestknownexamplesofgrowthfactorreceptorgeneamplificationareerbBanderbB-2.ThesearesometimesknownasepidermalgrowthfactorreceptorandHER2/neu.HER2/neugeneamplificationisanimportantabnormalityseeninaboutonethirdofbreastcancers.Bothoftheseoncogenesaretargetsofnewlydevelopedanti-cancertreatments.,SignaltransducersThesearetheintermediatepathwaysbetweenthegrowthfactorreceptorandthecellnucleuswherethesignalisreceived.Likegrowthfactorreceptors,thesecanbeturnedonoroff.Whentheyareabnormalincancercells,theyareturnedon.,TranscriptionfactorsThesearethefinalmoleculesinthechainthattellthecelltodivide.ThesemoleculesactontheDNAandcontrolwhichgenesareactiveinproducingRNAandprotein.,Thebestknownoftheseiscalledmyc.Inlungcancer,leukemia,lymphoma,andanumberofothercancertypes,mycisoftenoverlyactivatedandstimulatescelldivision.,Twowellknownsignaltransducersareablandras.Ablisactivatedinchronicmyelocyticleukemiaandisthetargetofthemostsuccessfuldrugforthisdisease,imatiniborGleevec.Abnormalitiesofrasarefoundinmanycancers.,ProgrammedcelldeathregulatorsThesemoleculespreventacellfromcommittingsuicidewhenitbecomesabnormal.Whenthesegenesareoveractivetheypreventthecellfromgoingthroughthesuicideprocess.,Thisleadstoanovergrowthofabnormalcells,whichcanthenbecomecancerous.Themostwelldescribedoneiscalledbcl-2.Itisoftenactivatedinlymphomacells.,3.TumorSuppressorGenes,Tumorsuppressorgenesarenormalgenesthatslowdowncelldivision,repairDNAmistakes,andtellcellswhentodie(aprocessknownasapoptosisorprogrammedcelldeath).,Whentumorsuppressorgenesdoworkproperly,cellscangrowoutofcontrol,whichcanleadtocancer.About30tumorsuppressorgeneshavebeenidentified,includingp53,BRCA1,BRCA2,APC,andRB1.Someofthesewillbedescribedinmoredetaillateron.,Atumorsuppressorgeneislikethebrakepedalonacaritnormallykeepsthecellfromdividingtooquicklyjustasabrakekeepsacarfromgoingtoofast.Whensomethinggoeswrongwiththegene,suchasamutation,celldivisioncangetoutofcontrol.,Animportantdifferencebetweenoncogenesandtumorsuppressorgenesisthatoncogenesresultfromtheactivation(turningon)ofproto-oncogenes,buttumorsuppressorgenescausecancerwhentheyareinactivated(turnedoff).,Anothermajordifferenceisthatwhiletheoverwhelmingmajorityofoncogenesdevelopfrommutationsinnormalgenes(proto-oncogenes)duringthelifeoftheindividual(acquiredmutations),abnormalitiesoftumorsuppressorgenescanbeinheritedaswellasacquired.,TypesofTumorSuppressorGenesGenesthatcontrolcelldivisionGenesthatrepairDNACellsuicidegenes,GenesthatcontrolcelldivisionSometumorsuppressorgeneshelpcontrolcellgrowthandreproduction.TheRB1(retinoblastoma)geneisanexampleofsuchagene.AbnormalitiesoftheRB1genecanleadtoatypeofeyecancer(retinoblastoma)ininfants,aswellastoothercancers.,GenesthatrepairDNAAsecondgroupoftumorsuppressorgenesisresponsibleforrepairingDNAdamage.Everytimeacellpreparestodivideinto2newcells,itmustduplicateitsDNA.,Thisprocessisnotperfect,andcopyingerrorssometimesoccur.Fortunately,cellshaveDNArepairgenes,whichmakeproteinsthatproofreadDNA.Butifthegenesresponsiblefortherepairarefaulty,thentheDNAcandevelopabnormalitiesthatmayleadtocancer.,WhenDNArepairgenesdowork,mutationscanslipby,allowingoncogenesandabnormaltumorsuppressorgenestobeproduced.ThegenesresponsibleforHNPCC(hereditarynonpolyposiscoloncancer)areexamplesofDNArepairgenedefects.WhenthesegenesdonotrepairtheerrorsinDNA,HNPCCcanresult.HNPCCaccountsforupto5%ofallcoloncancersandsomeendometrialcancers.,CellsuicidegenesIfthereistoomuchdamagetoacellDNAtobefixedbytheDNArepairgenes,thep53tumorsuppressorgeneisresponsiblefordestroyingthecellbyaprocesssometimesdescribedascellsuicide.,Othernamesforthisprocessareprogrammedcelldeathorapoptosis.Ifthep53geneisnotworkingproperly,cellswithDNAdamagethathasnotbeenrepairedcontinuetogrowandcaneventuallybecomecancerous.,Abnormalitiesofthep53genearesometimesinherited,suchasintheLi-Fraumenisyndrome(LFS).PeoplewithLFShaveahigherriskfordevelopinganumberofcancers,includingsoft-tissueandbonesarcomas,braintumors,breastcancer,adrenalglandcancer,andleukemia.,Manysporadic(notinherited)cancerssuchaslungcancers,coloncancers,breastcancersaswellasothersoftenhavemutatedp53geneswithinthetumor.,InheritedAbnormalitiesofTumorSuppressorGenesInheritedabnormalitiesoftumorsuppressorgeneshavebeenfoundinseveralcancersthattendtoruninfamilies.,Inadditiontomutationsinp53,RB1,andthegenesinvolvedinHNPCC,severalothermutationsintumorsuppressorgenescanbeinherited.,AdefectiveAPCgenecausesfamilialpolyposis,aconditioninwhichpeopledevelophundredsorthousandsofcolonpolyps,someofwhichmayeventuallyacquireseveralsporadicmutationsandturnintocoloncancer.,AbnormalitiesoftheBRCAgenesaccountfor5%to10%ofbreastcancers.Therearealsomanyotherexamplesofinheritedtumorsuppressorgenemutations,