医学遗传学16遗传与肿瘤发生

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1、医学遗传学16遗传与肿瘤发生16 遗传与肿瘤发生 Cancer GeneticsCancer GeneticsTheancientGreeksbelievedthatcancerwascausedbytoomuchbodyfluidtheycalledblackbile.Doctorsintheseventeenthandeighteenthcenturiessuggestedthatparasitescausedcancer.Today,doctorsunderstandmoreaboutthelinkbetweencancerandgenetics.Viruses,ultraviolet(

2、UV)radiation,andchemicalscanalldamagegenesinthehumanbody.Ifparticulargenesareaffected,apersoncandevelopcancer.Understandinghowgenescausecancer,though,firstrequiresabasicunderstandingofseveralgenetictermsandconcepts.1.GeneralCancerisaverycommondisease,affectingabout1in3individuals,andabouthalfthepeop

3、lethatcontractcancerwilldieasadirectresultoftheirdisease.Forthemostpart,cancerarisesfromasinglecell,thatis,cancerisaclonaldisease.Theaveragehumanbeingcontainsabout1014cells(i.e.,100,000,000,000,000cells),anyoneofwhichcould,inprinciple,becomeacancercell,ifitacquiredtherightsortofmutationswhileitstill

4、hadthepotentialtoproliferate.Therefore,thecancercellarisesandprogressesonceoutofapossible1014cellulartargets.Thatonlyhappensin1in3people.Eventhenitusuallytakes60or70yearstooccur.Tumors are hereditaryHereditary retinoblastoma isanautosomaldominanttraitinwhichsusceptibilitytoretinoblastomaisinherited.

5、ThisisanunusualdominanttraitinthatamutationinoneRBgeneisnotsufficienttocausesymptoms,butmutationsinthesecondalleleoftenariseduringdevelopment.Offspringhavea50%chanceofreceivingthemutantgenefromaheterozygousparent,and90%ofcarrierswilldevelopretinoblastoma,usuallyinbotheyes.Thehereditaryformisalsoasso

6、ciatedwithahighriskforothercancersespeciallyoftheboneandfibroustissues(osteosarcomasandfibrosarcoma.Sporadic retinoblastomaisatraitinwhichtheaffectedindividualhasnotinheritedanymutantallelesoftheretinoblastomagene.Themutationsoccurafterbirthandresultintumorformation.Tumorsusuallydevelopinonlyoneeyea

7、ndpatientsarenotathighriskforothercancers.Bothallelesneedtobemutatedinasinglecell,andthatiswhythisformtypicallyoccursonlyinoneeye.Chromosome and tumorsDetailedstudiesofthePhiladelphiachromosomeshowthatmostofchromosome22hasbeentranslocatedontothelongarmofchromosome9.Inaddition,thesmalldistalportionof

8、theshortarmofchromosome9istranslocatedtochromosome22.Thistranslocation,whichisfoundonlyintumorcells,indicatesthatapatienthaschronicmyelogenousleukemia(CML).InCML,thecellsthatproducebloodcellsforthebody(thehematopoieticcells)growuncontrollably,leadingtocancer.Theconnectionbetweenthischromosomalabnorm

9、alityandCMLwasclarifiedbystudyingthegeneslocatedonthechromosomesatthesitesofthetranslocationbreakpoints.Inoneofthetranslocatedchromosomes,partofagenecalledablismovedfromitsnormallocationonchromosome9toanewlocationonchromosome22.Thisbreakageandreattachmentleadstoanalteredablgene.Theproteinproducedfro

10、mthemutantablgenefunctionsimproperly,leadingtoCML.2.oncogeneOncogenesaremutatedformsofgenesthatcausenormalcellstogrowoutofcontrolandbecomecancercells.Theyaremutationsofcertainnormalgenesofthecellcalledproto-oncogenes.Proto-oncogenesarethegenesthatnormallycontrolhowoftenacelldividesandthedegreetowhic

11、hitdifferentiates(orspecializes).Whenaproto-oncogenemutates(changes)intoanoncogene,itbecomespermanentlyturnedonoractivatedwhenitisnotsupposedtobe.Whenthisoccurs,thecelldividestooquickly,whichcanleadtocancer.Itmaybehelpfultothinkofacellasacar.Forittoworkproperly,thereneedtobewaystocontrolhowfastitgoe

12、s.Aproto-oncogenenormallyfunctionsinawaythatissimilartoagaspedal-ithelpsthecellgrowanddivide.Anoncogenecouldbecomparedtoagaspedalthatisstuckdown,whichcausesthecelltodivideoutofcontrol.Thepathwayfornormalcellgrowthstartswithgrowth factor,whichlocksontoagrowth factor receptor.Thesignalfromthereceptori

13、ssentthroughasignal transducer.Atranscription factorisproduced,whichcausesthecelltobegindividing.Ifanyabnormalityisdetected,thecellismadetocommitsuicidebyaprogrammed cell death regulator.Morethan100oncogenesarenowrecognized,andundoubtedlymorewillbediscoveredinthefuture.Scientistshavedividedoncogenes

14、intothe5differentclasses.Growth factors Theseoncogenesproducefactorsthatstimulatecellstogrow.Thebestknownoftheseiscalledsis.Itleadstotheoverproductionofaproteincalledplatelet-derivedgrowthfactor,whichstimulatescellstogrow.Growth factor receptors These are normally turned on or off by growth factors.

15、When they are on,they stimulate the cell to grow.Certain mutations in the genes that produce these cause them to always be on.In other cases,the genes are lified.Thismeansthatinsteadoftheusual2copiesofthegene,theremaybeseveralextras,resultingintoomanygrowthfactorreceptormolecules.Asaresult,thecellsb

16、ecomeoverlysensitivetogrowth-promotingsignals.ThebestknownexlesofgrowthfactorreceptorgenelificationareerbBanderbB-2.ThesearesometimesknownasepidermalgrowthfactorreceptorandHER2/neu.HER2/neugenelificationisanimportantabnormalityseeninaboutonethirdofbreastcancers.Bothoftheseoncogenesaretargetsofnewlyd

17、evelopedanti-cancertreatments.Signal transducersThesearetheintermediatepathwaysbetweenthegrowthfactorreceptorandthecellnucleuswherethesignalisreceived.Likegrowthfactorreceptors,thesecanbeturnedonoroff.Whentheyareabnormalincancercells,theyareturnedon.Transcription factorsThesearethefinalmoleculesinth

18、echainthattellthecelltodivide.ThesemoleculesactontheDNAandcontrolwhichgenesareactiveinproducingRNAandprotein.Thebestknownoftheseiscalledmyc.Inlungcancer,leukemia,lymphoma,andanumberofothercancertypes,mycisoftenoverlyactivatedandstimulatescelldivision.Twowellknownsignaltransducersareablandras.Ablisac

19、tivatedinchronicmyelocyticleukemiaandisthetargetofthemostsuccessfuldrugforthisdisease,imatiniborGleevec.Abnormalitiesofrasarefoundinmanycancers.Programmed cell death regulatorsThesemoleculespreventacellfromcommittingsuicidewhenitbecomesabnormal.Whenthesegenesareoveractivetheypreventthecellfromgoingt

20、hroughthesuicideprocess.Thisleadstoanovergrowthofabnormalcells,whichcanthenbecomecancerous.Themostwelldescribedoneiscalledbcl-2.Itisoftenactivatedinlymphomacells.3.Tumor Suppressor Genes Tumor suppressor genesarenormalgenesthatslowdowncelldivision,repairDNAmistakes,andtellcellswhentodie(aprocessknow

21、nasapoptosisorprogrammedcelldeath).Whentumorsuppressorgenesdoworkproperly,cellscangrowoutofcontrol,whichcanleadtocancer.About30tumorsuppressorgeneshavebeenidentified,includingp53,BRCA1,BRCA2,APC,and RB1.Someofthesewillbedescribedinmoredetaillateron.Atumorsuppressorgeneislikethebrakepedalonacaritnorm

22、allykeepsthecellfromdividingtooquicklyjustasabrakekeepsacarfromgoingtoofast.Whensomethinggoeswrongwiththegene,suchasamutation,celldivisioncangetoutofcontrol.Animportantdifferencebetweenoncogenesandtumorsuppressorgenesisthatoncogenesresultfromtheactivation(turningon)ofproto-oncogenes,buttumorsuppress

23、orgenescausecancerwhentheyareinactivated(turnedoff).Anothermajordifferenceisthatwhiletheoverwhelmingmajorityofoncogenesdevelopfrommutationsinnormalgenes(proto-oncogenes)duringthelifeoftheindividual(acquiredmutations),abnormalitiesoftumorsuppressorgenescanbeinheritedaswellasacquired.Types of Tumor Su

24、ppressor GenesGenesthatcontrolcelldivisionGenesthatrepairDNACellsuicidegenesGenes that control cell division Some tumor suppressor genes help control cell growth and reproduction.The RB1(retinoblastoma)gene is an exle of such a gene.Abnormalities of the RB1 gene can lead to a type of eye cancer(reti

25、noblastoma)in infants,as well as to other cancers.Genes that repair DNAAsecondgroupoftumorsuppressorgenesisresponsibleforrepairingDNAdamage.Everytimeacellpreparestodivideinto2newcells,itmustduplicateitsDNA.Thisprocessisnotperfect,andcopyingerrorssometimesoccur.Fortunately,cellshaveDNA repair genes,w

26、hichmakeproteinsthatproofreadDNA.Butifthegenesresponsiblefortherepairarefaulty,thentheDNAcandevelopabnormalitiesthatmayleadtocancer.WhenDNArepairgenesdowork,mutationscanslipby,allowingoncogenesandabnormaltumorsuppressorgenestobeproduced.ThegenesresponsibleforHNPCC(hereditarynonpolyposiscoloncancer)a

27、reexlesofDNArepairgenedefects.WhenthesegenesdonotrepairtheerrorsinDNA,HNPCCcanresult.HNPCCaccountsforupto5%ofallcoloncancersandsomeendometrialcancers.Cell suicide genesIfthereistoomuchdamagetoacellDNAtobefixedbytheDNArepairgenes,thep53tumorsuppressorgeneisresponsiblefordestroyingthecellbyaprocesssom

28、etimesdescribedascellsuicide.Othernamesforthisprocessareprogrammed cell deathorapoptosis.Ifthep53geneisnotworkingproperly,cellswithDNAdamagethathasnotbeenrepairedcontinuetogrowandcaneventuallybecomecancerous.Abnormalitiesofthep53genearesometimesinherited,suchasintheLi-Fraumeni syndrome(LFS).Peoplewi

29、thLFShaveahigherriskfordevelopinganumberofcancers,includingsoft-tissueandbonesarcomas,braintumors,breastcancer,adrenalglandcancer,andleukemia.Manysporadic(notinherited)cancerssuchaslungcancers,coloncancers,breastcancersaswellasothersoftenhavemutatedp53geneswithinthetumor.Inherited Abnormalities of T

30、umor Suppressor Genes Inheritedabnormalitiesoftumorsuppressorgeneshavebeenfoundinseveralcancersthattendtoruninfamilies.Inadditiontomutationsinp53,RB1,andthegenesinvolvedinHNPCC,severalothermutationsintumorsuppressorgenescanbeinherited.AdefectiveAPCgenecausesfamilial polyposis,aconditioninwhichpeople

31、develophundredsorthousandsofcolonpolyps,someofwhichmayeventuallyacquireseveralsporadicmutationsandturnintocoloncancer.AbnormalitiesoftheBRCAgenesaccountfor5%to10%ofbreastcancers.Therearealsomanyotherexlesofinheritedtumorsuppressorgenemutations,andmorearebeingdiscoveredeachyear.Non-inherited mutation

32、s of tumor suppressor genesMutationsoftumorsuppressorgeneshavebeenfoundinmanycancers.Forexle,abnormalitiesofthep53genehavebeenfoundinover50%ofhumancancers.Acquiredmutations(thosewhichhappenduringapersonlife)ofthep53geneappeartobeinvolvedinawiderangeofcancers,includinglung,colorectal,andbreastcancer,

33、aswellasmanyothers.Thep53geneisbelievedtobeamongthemostfrequentlymutatedgenesinhumancancer.However,acquiredchangesinmanyothertumorsuppressorgenesalsocontributetothedevelopmentofsporadic(notinherited)cancers.Inherited cancer Abnormal gene Other non-inherited cancers seen with this geneRetinoblastomaR

34、BIMany different cancers Li-Fraumeni Syndrome(sarcomas,brain tumors,leukemia)P53Many different cancersMelanomaINK4aMany different cancersColorectal cancer(due to familial polyposis)APCMost colorectal cancersColorectal cancer(without polyposis)MLH1,MSH2,or MSH6Colorectal,gastric,endometrial cancers B

35、reast and/or ovarianBRCA1,BRCA2Only rare ovarian cancersWilms TumorWTIWilms tumorsNerve tumors,including brainNF1,NF2Small numbers of colon cancers,melanomas,neuroblastomaKidney cancerVHLCertain types of kidney cancersOncogene/Tumor Suppressor GeneRelated CancersBRCA1,BRCA2Breast and ovarian cancerb

36、cr-ablChronic myelogenous leukemiabcl-2B-cell lymphomaHER2/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 cancers4.Multi-stageCarci

37、nogenesisMulti-stagecarcinogenesisstartswiththedevelopmentofinitiatedcellsafterinteractionsofacarcinogenicagentwithnormal(target)cells.Theinitiatedcellshavetheabilitytoclonallyexpandandactasprecursorsforadditionalalterations.Indifferentmodelsystemsinitiatedcellshaveshownsomeofthefollowingcharacteristics.1.Increasedproliferativecapabilities2.Resistancetoapoptoticstimuli3.Resistancetootherinducersofcelltoxicity4.Increasedlife-span