医学遗传学16肿瘤遗传学engv.ppt

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1、Medical Genetics16 遗传与肿瘤发生 Cancer GeneticsCancer GeneticsMedical GeneticsTheancientGreeksbelievedthatcancerwascausedbytoomuchbodyfluidtheycalledblackbile.Medical GeneticsDoctorsintheseventeenthandeighteenthcenturiessuggestedthatparasitescausedcancer.Today,doctorsunderstandmoreaboutthelinkbetweencanc

2、erandgenetics.Medical GeneticsViruses,ultraviolet(UV)radiation,andchemicalscanalldamagegenesinthehumanbody.Ifparticulargenesareaffected,apersoncandevelopcancer.Understandinghowgenescausecancer,though,firstrequiresabasicunderstandingofseveralgenetictermsandconcepts.Medical Genetics1.GeneralCancerisav

3、erycommondisease,affectingabout1in3individuals,andabouthalfthepeoplethatcontractcancerwilldieasadirectresultoftheirdisease.Medical GeneticsForthemostpart,cancerarisesfromasinglecell,thatis,cancerisaclonaldisease.Theaveragehumanbeingcontainsabout1014cells(i.e.,100,000,000,000,000cells),anyoneofwhichc

4、ould,inprinciple,becomeacancercell,ifitacquiredtherightsortofmutationswhileitstillhadthepotentialtoproliferate.Medical GeneticsTherefore,thecancercellarisesandprogressesonceoutofapossible1014cellulartargets.Thatonlyhappensin1in3people.Eventhenitusuallytakes60or70yearstooccur.Medical GeneticsMedical

5、GeneticsTumors are hereditaryHereditary retinoblastoma isanautosomaldominanttraitinwhichsusceptibilitytoretinoblastomaisinherited.ThisisanunusualdominanttraitinthatamutationinoneRBgeneisnotsufficienttocausesymptoms,butmutationsinthesecondalleleoftenariseduringdevelopment.Medical GeneticsMedical Gene

6、ticsOffspringhavea50%chanceofreceivingthemutantgenefromaheterozygousparent,and90%ofcarrierswilldevelopretinoblastoma,usuallyinbotheyes.Thehereditaryformisalsoassociatedwithahighriskforothercancersespeciallyoftheboneandfibroustissues(osteosarcomasandfibrosarcoma.Medical Genetics Sporadic retinoblasto

7、maisatraitinwhichtheaffectedindividualhasnotinheritedanymutantallelesoftheretinoblastomagene.Medical GeneticsThemutationsoccurafterbirthandresultintumorformation.Tumorsusuallydevelopinonlyoneeyeandpatientsarenotathighriskforothercancers.Bothallelesneedtobemutatedinasinglecell,andthatiswhythisformtyp

8、icallyoccursonlyinoneeye.Medical GeneticsMedical GeneticsChromosome and tumorsDetailedstudiesofthePhiladelphiachromosomeshowthatmostofchromosome22hasbeentranslocatedontothelongarmofchromosome9.Inaddition,thesmalldistalportionoftheshortarmofchromosome9istranslocatedtochromosome22.Thistranslocation,wh

9、ichisfoundonlyintumorcells,indicatesthatapatienthaschronicmyelogenousleukemia(CML).InCML,thecellsthatproducebloodcellsforthebody(thehematopoieticcells)growuncontrollably,leadingtocancer.Medical GeneticsMedical GeneticsMedical GeneticsTheconnectionbetweenthischromosomalabnormalityandCMLwasclarifiedby

10、studyingthegeneslocatedonthechromosomesatthesitesofthetranslocationbreakpoints.Medical GeneticsInoneofthetranslocatedchromosomes,partofagenecalledablismovedfromitsnormallocationonchromosome9toanewlocationonchromosome22.Thisbreakageandreattachmentleadstoanalteredablgene.Theproteinproducedfromthemutan

11、tablgenefunctionsimproperly,leadingtoCML.Medical Genetics2.oncogeneOncogenesaremutatedformsofgenesthatcausenormalcellstogrowoutofcontrolandbecomecancercells.Theyaremutationsofcertainnormalgenesofthecellcalledproto-oncogenes.Medical GeneticsProto-oncogenesarethegenesthatnormallycontrolhowoftenacelldi

12、videsandthedegreetowhichitdifferentiates(orspecializes).Whenaproto-oncogenemutates(changes)intoanoncogene,itbecomespermanentlyturnedonoractivatedwhenitisnotsupposedtobe.Whenthisoccurs,thecelldividestooquickly,whichcanleadtocancer.Medical GeneticsItmaybehelpfultothinkofacellasacar.Forittoworkproperly

13、,thereneedtobewaystocontrolhowfastitgoes.Aproto-oncogenenormallyfunctionsinawaythatissimilartoagaspedal-ithelpsthecellgrowanddivide.Anoncogenecouldbecomparedtoagaspedalthatisstuckdown,whichcausesthecelltodivideoutofcontrol.Medical GeneticsThepathwayfornormalcellgrowthstartswithgrowth factor,whichloc

14、ksontoagrowth factor receptor.Thesignalfromthereceptorissentthroughasignal transducer.Atranscription factorisproduced,whichcausesthecelltobegindividing.Ifanyabnormalityisdetected,thecellismadetocommitsuicidebyaprogrammed cell death regulator.Medical GeneticsMorethan100oncogenesarenowrecognized,andun

15、doubtedlymorewillbediscoveredinthefuture.Scientistshavedividedoncogenesintothe5differentclasses.Medical GeneticsGrowth factors Theseoncogenesproducefactorsthatstimulatecellstogrow.Thebestknownoftheseiscalledsis.Itleadstotheoverproductionofaproteincalledplatelet-derivedgrowthfactor,whichstimulatescel

16、lstogrow.Medical GeneticsGrowth factor receptorsThesearenormallyturnedonoroffbygrowthfactors.Whentheyareon,theystimulatethecelltogrow.Certainmutationsinthegenesthatproducethesecausethemtoalwaysbeon.Inothercases,thegenesareamplified.Medical GeneticsThismeansthatinsteadoftheusual2copiesofthegene,there

17、maybeseveralextras,resultingintoomanygrowthfactorreceptormolecules.Asaresult,thecellsbecomeoverlysensitivetogrowth-promotingsignals.Medical GeneticsThebestknownexamplesofgrowthfactorreceptorgeneamplificationareerb Banderb B-2.ThesearesometimesknownasepidermalgrowthfactorreceptorandHER2/neu.HER2/neug

18、eneamplificationisanimportantabnormalityseeninaboutonethirdofbreastcancers.Bothoftheseoncogenesaretargetsofnewlydevelopedanti-cancertreatments.Medical GeneticsSignal transducersThesearetheintermediatepathwaysbetweenthegrowthfactorreceptorandthecellnucleuswherethesignalisreceived.Likegrowthfactorrece

19、ptors,thesecanbeturnedonoroff.Whentheyareabnormalincancercells,theyareturnedon.Medical GeneticsTranscription factorsThesearethefinalmoleculesinthechainthattellthecelltodivide.ThesemoleculesactontheDNAandcontrolwhichgenesareactiveinproducingRNAandprotein.Medical GeneticsThebestknownoftheseiscalledmyc

20、.Inlungcancer,leukemia,lymphoma,andanumberofothercancertypes,mycisoftenoverlyactivatedandstimulatescelldivision.Medical GeneticsTwowellknownsignaltransducersareablandras.Ablisactivatedinchronicmyelocyticleukemiaandisthetargetofthemostsuccessfuldrugforthisdisease,imatiniborGleevec.Abnormalitiesofrasa

21、refoundinmanycancers.Medical GeneticsProgrammed cell death regulatorsThesemoleculespreventacellfromcommittingsuicidewhenitbecomesabnormal.Whenthesegenesareoveractivetheypreventthecellfromgoingthroughthesuicideprocess.Medical GeneticsThisleadstoanovergrowthofabnormalcells,whichcanthenbecomecancerous.

22、Themostwelldescribedoneiscalledbcl-2.Itisoftenactivatedinlymphomacells.Medical Genetics3.Tumor Suppressor Genes Tumor suppressor genesarenormalgenesthatslowdowncelldivision,repairDNAmistakes,andtellcellswhentodie(aprocessknownasapoptosisorprogrammedcelldeath).Medical GeneticsWhentumorsuppressorgenes

23、doworkproperly,cellscangrowoutofcontrol,whichcanleadtocancer.About30tumorsuppressorgeneshavebeenidentified,includingp53,BRCA1,BRCA2,APC,and RB1.Someofthesewillbedescribedinmoredetaillateron.Medical GeneticsAtumorsuppressorgeneislikethebrakepedalonacaritnormallykeepsthecellfromdividingtooquicklyjusta

24、sabrakekeepsacarfromgoingtoofast.Whensomethinggoeswrongwiththegene,suchasamutation,celldivisioncangetoutofcontrol.Medical GeneticsAnimportantdifferencebetweenoncogenesandtumorsuppressorgenesisthatoncogenesresultfromtheactivation(turningon)ofproto-oncogenes,buttumorsuppressorgenescausecancerwhentheya

25、reinactivated(turnedoff).Medical GeneticsAnothermajordifferenceisthatwhiletheoverwhelmingmajorityofoncogenesdevelopfrommutationsinnormalgenes(proto-oncogenes)duringthelifeoftheindividual(acquiredmutations),abnormalitiesoftumorsuppressorgenescanbeinheritedaswellasacquired.Medical GeneticsTypes of Tum

26、or Suppressor GenesGenesthatcontrolcelldivisionGenesthatrepairDNACellsuicidegenesMedical GeneticsGenes that control cell divisionSometumorsuppressorgeneshelpcontrolcellgrowthandreproduction.TheRB1(retinoblastoma)geneisanexampleofsuchagene.AbnormalitiesoftheRB1genecanleadtoatypeofeyecancer(retinoblas

27、toma)ininfants,aswellastoothercancers.Medical GeneticsGenes that repair DNAAsecondgroupoftumorsuppressorgenesisresponsibleforrepairingDNAdamage.Everytimeacellpreparestodivideinto2newcells,itmustduplicateitsDNA.Medical GeneticsThisprocessisnotperfect,andcopyingerrorssometimesoccur.Fortunately,cellsha

28、veDNA repair genes,whichmakeproteinsthatproofreadDNA.Butifthegenesresponsiblefortherepairarefaulty,thentheDNAcandevelopabnormalitiesthatmayleadtocancer.Medical GeneticsWhenDNArepairgenesdowork,mutationscanslipby,allowingoncogenesandabnormaltumorsuppressorgenestobeproduced.ThegenesresponsibleforHNPCC

29、(hereditarynonpolyposiscoloncancer)areexamplesofDNArepairgenedefects.WhenthesegenesdonotrepairtheerrorsinDNA,HNPCCcanresult.HNPCCaccountsforupto5%ofallcoloncancersandsomeendometrialcancers.Medical GeneticsCell suicide genesIfthereistoomuchdamagetoacellDNAtobefixedbytheDNArepairgenes,thep53tumorsuppr

30、essorgeneisresponsiblefordestroyingthecellbyaprocesssometimesdescribedascellsuicide.Medical GeneticsOthernamesforthisprocessareprogrammed cell deathorapoptosis.Ifthep53geneisnotworkingproperly,cellswithDNAdamagethathasnotbeenrepairedcontinuetogrowandcaneventuallybecomecancerous.Medical GeneticsAbnor

31、malitiesofthep53genearesometimesinherited,suchasintheLi-Fraumeni syndrome(LFS).PeoplewithLFShaveahigherriskfordevelopinganumberofcancers,includingsoft-tissueandbonesarcomas,braintumors,breastcancer,adrenalglandcancer,andleukemia.Medical GeneticsManysporadic(notinherited)cancerssuchaslungcancers,colo

32、ncancers,breastcancersaswellasothersoftenhavemutatedp53geneswithinthetumor.Medical GeneticsInherited Abnormalities of Tumor Suppressor Genes Inheritedabnormalitiesoftumorsuppressorgeneshavebeenfoundinseveralcancersthattendtoruninfamilies.Medical GeneticsInadditiontomutationsinp53,RB1,andthegenesinvo

33、lvedinHNPCC,severalothermutationsintumorsuppressorgenescanbeinherited.Medical GeneticsAdefectiveAPCgenecausesfamilial polyposis,aconditioninwhichpeopledevelophundredsorthousandsofcolonpolyps,someofwhichmayeventuallyacquireseveralsporadicmutationsandturnintocoloncancer.Medical GeneticsAbnormalitiesof

34、theBRCAgenesaccountfor5%to10%ofbreastcancers.Therearealsomanyotherexamplesofinheritedtumorsuppressorgenemutations,andmorearebeingdiscoveredeachyear.Medical GeneticsNon-inherited mutations of tumor suppressor genesMutationsoftumorsuppressorgeneshavebeenfoundinmanycancers.Medical GeneticsForexample,ab

35、normalitiesofthep53genehavebeenfoundinover50%ofhumancancers.Acquiredmutations(thosewhichhappenduringapersonlife)ofthep53geneappeartobeinvolvedinawiderangeofcancers,includinglung,colorectal,andbreastcancer,aswellasmanyothers.Medical GeneticsThep53geneisbelievedtobeamongthemostfrequentlymutatedgenesin

36、humancancer.However,acquiredchangesinmanyothertumorsuppressorgenesalsocontributetothedevelopmentofsporadic(notinherited)cancers.Medical GeneticsInherited cancer Abnormal gene Other non-inherited cancers seen with this geneRetinoblastomaRBIMany different cancers Li-Fraumeni Syndrome(sarcomas,brain tu

37、mors,leukemia)P53Many different cancersMelanomaINK4aMany different cancersColorectal cancer(due to familial polyposis)APCMost colorectal cancersColorectal cancer(without polyposis)MLH1,MSH2,or MSH6Colorectal,gastric,endometrial cancers Breast and/or ovarianBRCA1,BRCA2Only rare ovarian cancersWilms T

38、umorWTIWilms tumorsNerve tumors,including brainNF1,NF2Small numbers of colon cancers,melanomas,neuroblastomaKidney cancerVHLCertain types of kidney cancersMedical GeneticsOncogene/Tumor Suppressor GeneRelated CancersBRCA1,BRCA2Breast and ovarian cancerbcr-ablChronic myelogenous leukemiabcl-2B-cell l

39、ymphomaHER2/neu(erbB-2)Breast cancer,ovarian cancer,othersN-mycNeuroblastomaEWSEwing tumorC-mycBurkitt lymphoma,othersp53Brain tumors,skin cancers,lung cancer,head and neck cancers,othersMLH1,MSH2Colorectal cancersAPCColorectal cancersMedical Genetics4.Multi-stageCarcinogenesisMulti-stagecarcinogene

40、sisstartswiththedevelopmentofinitiatedcellsafterinteractionsofacarcinogenicagentwithnormal(target)cells.Theinitiatedcellshavetheabilitytoclonallyexpandandactasprecursorsforadditionalalterations.Indifferentmodelsystemsinitiatedcellshaveshownsomeofthefollowingcharacteristics.1.Increasedproliferativecapabilities2.Resistancetoapoptoticstimuli3.Resistancetootherinducersofcelltoxicity4.Increasedlife-spanMedical GeneticsMedical GeneticsMedical GeneticsMedical GeneticsMedical Genetics