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Three differenttypes of approaches appear particularly promising.1. comparatiue genomic hybridization (cGH) uses fluorescent labeling offragments of DNA extracted from normal cells and from cancer cells toidentify regions of the genome that are amplified or deleted in a given tlpeof cancer (Figure 20-35). The labeled fragments are allowed to hybridize toDNA microarrays in which each spot corresponds to a known location inthe normal genome.
Different spots light up in different fluorescent colors,Figure20-35 Comparativegenomichybridizationfor detectionof the DNAchangesin tumor cells.(A)DNAfragmentsfromtumor cellsand normalcellsarelabeledwith two differentmolecules(redfor the tumor,fluorescentgreenforrhenormalcontrol)andin whichhybridizedto a DNAmicroarrayto a definedeachspotcorresPondspositionin the normalgenome'(B)Theratiosof red to greenfluorescenceforeachspot is plottedasshownbelowtodefinetho:;eregionsamplifiedor deletedin the tum,crcells.A redsignalindicatesan amplification,while a greensignala ,Celetion.siqnifiesrumorilssueIIg e n o m i cD N A i s o l a t e da n dfluorescentlylabeledI+location of Myc ge^eao2aIt.,t i9enelosstiMyc DNADNAmicroarray(B)amolificationIonlgene100806040d i s t a n c ei n m e g a b a s easl o n g c h r o m o s o m e1201240Chapter20:Canceraccording to the ratio of normal to cancerous labeled fragments that bind tothem.
In this way, one can locate regions of the cancer cell genome that havebeen amplified or deleted. one then searches -or" ,ru.roirly for candidategeneswithin these regions that may contribute to cancer development.2. DNA microarrays can also be used to reveal specific changes in geneexpression associated with cancer. In this case, a cell's population ofmRNAs is used to prepare the probe for hybridization, rather than its chromosomal DNA (seeFigure 8-76).p.
571). This provides an efficient way, in principle, to identify any tumorsuppressor gene whose loss promotes cancerous transformation in theparticular animal or cell line being tested.\Arhateverthe approach used to identify a new candidate cancer-criticalgene, it remains a challenge to determine whether the gene really contributesto cancer causation. Testing for the effects of an overexpression of candidateoncogenes or an inhibition of candidate tumor suppressor genes in cell cultureassays can help. But more convincing tests use transgenic mice that overexpress candidate oncogenes and knockout mice that lack candidate tumor suppressor genes.
In both types of mice, cancer development should be accelerated if the genes are real culprits.Sum m a r yCancer-criticalgenescan be classifiedinto two groups,according to whether their gainof function or their lossof function contributes to cancerdeuelopment.Gain-of-finction mutations that conuert proto-oncogenesto oncogenesstimulate cellsto increasetheir numberswhen theyshould not; loss-of-functionmutations of tumor suppressorgenesabolish the inhibitory controlsthat normally hetp to hold cetlnumbersin check.oncogeneshaue a dominant genetic ffict, and many of them werefirst discoueredbecausethey causecancer in animals when introduced by a retrouirui that originallypicked up a normal form of the gene (a proto-oncogene)from a preuious host cell.Oncogenescan also be identified by characteristicchromosomal aberrations that canactiuate a proto- oncogene.suppressorgene.wzluo puedep ]Inpe uB se esuBualuleru sll pue plulue JPlnlleJlllnlu E Jo ]ueuclo-le^ap aql qlog 'srsElsoauoq ureluleru puE JeAouJn]IIaJ IoJluoc o] dpoq llnpBIuruJou eq] ur alBJedo luaudola^ap 3luo,{Jqrua IoJluoJ }eq} susluPqJeu SuIlBu'tZ-8rsa,,usy'asr.rdrnsou sI qqt 'lq81spu1qqll6Jaldeq3urssnJSIparueseq]'sdem.qledasaqlJo lsEI aql Jo gud Suraq sEUqllm-saua8 pcrtrJJ-Jeouec,,(qpapocua sluauodruoo epnloul 1e sdeatqted 3u1pu-8rs aseuq aursor,,hrotdacar pue 'qcloN 'flgg;'Soqa8peH ']uM alfl i(ZZ pup gIsraldeq3 ur pessnf,srp) luarudolanap Surrnp eleJlunluruoc slleJ qtlqm q8norqls,,(ervrqtedSuqeu8rs rofeur aq] 1e ,,typcncerd;o sluauodruoJ apnlJu saldurexg'luaurdolanap cruofrqure ur aloJ rlaq] JoJ rrlv\oDl dpearp sauaB;o sSolouroq'lxeluooare 'aldruexa ro; 'saua8 rossarddns Jolunl pue sauaSoruo ,{ue4aq o} lno suJn} uauo }l teJueo JoJIeOI}IJJse pauJaqloue ur sarpnls ruo{ JEIITtUEJ'sllal-puaprqJnru,lrou>Iarlr depolaJou\.lrauEuaqossraua8lnoqeleql'sr(e,r,rqledSuleu8rs JelnllateJlul;o luauodruoce sE qg-sllal pruJou ut sutalord asaqllEJlueJ p sE seg pup Jolrqrqu a1c^,{c-gacJo eloJ da>1aqr pelealal leql selpnls ro; ]utod SuDrets eql sem qJJEeseJJecuuJ'seg pup qU qloq rog ',{-ralsdure spl\ sllec raoueJ JoIPtuJou Jeq}la uI pauol}f,uryuralord seg aql rvroqlnq 'arn11ncut .{laleudorddeur pue ,tlazrtssacxaalera;qord'seruolselqoulleJol slleJ llaJrp o] Ulr,rotnlsem aua8 luelnru eql 'szyJo asec aq] uIur palelnu sem ]I ]eq] se^ rrrltoDl se^ leql 1e 'ayduexa ro; 'pauolc [1eu-r8rro sem aua8 qy aql ueq iysllar JaJupJ Jo JIlsIJelJEJEqcsJoIABqaqlueJJeqeaqt ol alnqlJluor aua8 aql uI suollelnlu ,lroq pue slleJ Ierurou ut suorlcury aua8eq] ,lroq qloq puetsJapun o] paau allr SecueJ e uI palelntu sI leql aua8 e uanrSseue9le)!lu)-re)ue)Jo uoll)unl eql lo^o)un ol pedlaHe^eHe)!wqloSro serpnlspareeur6uSIlle)tlauagpupso^tqurf6urdo;ana6'asJo^ srlpql Jeqloue ol Jor eqaq peq;o uraped euo ruoq eAIoAao] Jorunl B salqeue saua8 pctlrrc-JeJuec ur sa8ueqc'aldruexa pepualxe uB sp JaJuBc uoloJ SurssncJo uorssaoJns p laoq Sulr,roqs-s1pdq uorlJes aql pue aM'paurruJalap eq ueJ JaJuEl Jo xaluoJ aql u1 saua8asaql Jo suorlounJ er{l ,vrorl pue sauaB IeJI}rJJ-ref,ueJ uI suollelnru ruoq esIJBsJor eqeqsru f,llsFalf,EJeqJasaql l oq JepISuoJ a,lr 'uoIJJas slql q 'sdeldsrpIIeJ JeJueJE leqt sror^EqaqsrruJospuH eql palslTpuE snoJacuPJIIec B e{eu }uqlsauradord praua8 aq] pazrJprurunse,vrtaldeqc slq] Jo uollJes ISJIJeql uI'JarueJ Surpuelsrapun Jno poruJoJsueJ]seq d8oJo-lorq IIaJ Jo slcadse crspq uo qf,Jeasar'Llasranuoc:qoJpeseJJeJuEf,Jo lcnporddqe sB peuJual uaeq seq ruaql lnoqe MouI e,vr leqm Jo qlnlN 's[ert xaldurocur luapuadapJalur pup paluu are sLearqled snorJel aql'(6I raldeq3 uI pessnJ-srp) sJoqq8reu slr qlIM suollJeJalul IPJIuPqoeruJo 191raldeq3 uI passnJslp)sluarueloru s,lleJ eq] urano8 sraqlo illls 1(8I raldeq3 uI pessnf,slp)qreap ilacro (11 raldeq3 ur passnJsrp)elJltJ IIer aq] Iortuor ]eqt esoql se qJns 'surerSordIeuJetur s,lleJeql ro; alqrsuodsareru sraqlo :191ratdeq3 uI passnJslp)tuauuoJ-rluap,{anuocu1srterr,rqledeql Jo eruoss,llaf,ruo{spu8rsJeJueJ}uelrodrur'sde,nnqtedrfuoleln8ar puepcruaqcorq luaJaJJrpur lJe leql saua8 pcrlrrJ-JacupJ uaamleq 1nq 'sauaSocuo-olo.rd pue saua8 rossarddns-rournl uaamlaq lou sr uopcupslp luepodur aql'uorlounJ sllac JaJuEr lrroq puets'scrlaua8JelnraloruJo sruJet ur srql op ol pue'sluauodruoc (rossarddns Journt) ,fuo4qlqq pue (aua8-rapun ol sr urre eq]JI-ocuo-olord) [ro1e1nur1sq]oq eAEqsrusrueqJeuJelnllaf,lsoru asnef,eqIo4uoc'saua8 sselJ Jaqlra ur suorlplnru ruoq llnseJ ueJ Jorleqeqilac uo slJeJJeJoJospur) alups aqJ 'uroJ atUESaqt Jo seprs ollu are ,taql '^\er^ Jo lurod s,lac JesuEJe tuoq '1ng dlluarag;Ip-uraqt lJeJJe tBql sa8uuqc cpaua8rda pue suollelntuaq] pue-saua8 rossarddnsJoun] pu? 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