UnitTwentyThreeVirusesandOncogenesOverviewFivegroupsofdouble-strandedDNAvirusesanddiploidRNAvirusesoftheretroviralgroupareassociatedepidemiologically,experimentally,orbothwithanimalandhumanneoplasia.DNAtumorvirusesassociatedwithcanceronepidemiologicalgroundsincludepapillomavirusesandurogenitalcancer,herpesvirusesandBurkitt'slymphomaandnasopharyngeal-carcinoma,andhepatitisvirusesandlivercancer.Nobiochemicallydefinedoncogeneshaveyetbeendescribedforanyoftheseviruses;however,preliminaryevidencesuggeststheexistenceoftransformingsequencesinbothpapillomaandherpesviruses.Althoughstudiedingreatmoleculardetailwithelucidationofclearlydefinedoncogenes,polyomavirusesandadenoviruseshavenotbeenassociatedwithnaturallyoccurringtumorsinvivo.Theironcogenesarestructurallydissimilartoretroviraloncogenes,yetthesetwogeneclassesappeartosubservesimilarfunctions.TheRNAtumorviruseswerethefirstinfectiousagentsunequivocallyassociatedwithneoplasia.Alargenumberofsuchviruseshavebeenisolatedfromchickens,rodents,cats,andmonkeys.Manytransduceoneortwooncogenesequencesnecessaryandsufficientforefficientcellulartransformation.Theseoncogeneswerederivedoriginallyfromhostsequences.Virallytransducedoncogenescomprisesome20independentspeciesfallingintoasmallernumber(somefivetoseven)offunctionalcategories.Theretrovirallifecycle,employingadouble-strandedDNAintermediate(theprovirus)thatintegratesintohostDNA,suggestsamechanismwherebytheviruscouldacquirecellularsequences.BothRNAandDNAvirusesareassociatedwithcancer.TherearefivemajorcategoriesofDNArumorviruses,eachofwhichhasadouble-strandedDNAgenome.Noknownsingle-strandedDNAvirusisassociatedwithoncogenesis.OftheRNAviruses,onlyonegroupisassociatedwithcancer:thesingle-strandedbutdiploidoncornaviruses.OncogenesandHumanCancelsOverviewNearlyalloftheknownretroviraloncogeneshaveproto-oncogenecounterpartsdetectableinhumanDNA.Manyoftheseproto-oncogenesactivatedthroughavarietyofmechanismshavebeenassociatedwithhumancancers.Perturbationsinthestructureorexpressionofcertainproto-oncogenesappeartobethegeneralmeansbywhichthisactivationoccurs.Examplesofstructuralchangesareseeninsingleaminoacidsubstitutionsintherasfamilyofgenesisolatedironhumanleukemias,coloncarcinomas,andbladdercarcinomas.Inchronicmyelogenousleukemia,thetranslocationbetweenchromosomes9qand22qresultsintheformationofanovelfusiongenetermedbcr-ablwhosegeneproductdiffersfromthatofthenormalc-ablproteininsizeandintheabilitytoautophosphorylate.Perturbationsintheexpressionofaproto-oncogenecanbeduetothepresenceofabnormalregulatoryelementsasinthecaseoftranslocationsinvolvingc-mycseeninBurkitt'slymphomas,orduetoamplificationwhichaugmentsexpressionbyincreasingthegenecopynumber.AmplificationsofN-mycinneuroblastoma,anderB-/neuinhumanbreastcancerhavebeencorrelatedwithamoreadvancedstageandapoorerprognosis.Recently,specifcgeneticelementswhichsuppesstumorigencityhavebeendescribed.Severalsuchelementshavebeenlocalizedtohumanchromosomes11and13qleadingtotheconceptualizationofcancersuppressorgenes.Inthisparadigm,thelossofbothallelesofsuchasuppressorgene,ratherthanthe"activation"ofaproto-oncogene,isresponsiblefortumorigenesis.Inhumanretinoblastomas,theinactivationofaspecificgeneonchromosome13q,calledrb-l,iscriticalforneoplastictransformation.Ineachcasedescribed,perturbationsinanyonegenemaybeinvolvedindifferentphases(earlyorlate)ofoncogenesisdependingonthediseasecontext.Also,quitefrequently,manygeneticabnormalitiesareassociatedwithatumorthatobscuresthesignificanceofanysinglegeneticchange.Furthermore,relianceonanimalmodelsystemstoexplainhumanmalignancymustbetakenwithsomecautionsinceevidenceexistsimplicatingdifferentoncogenesinthegenesisofsimilartumorsdependingonthespeciesstudied(manvs.mouse).Tothispoint,wehavesuggestedsomeassociationsbetweenoncogenesandtheneoplasticstate.Whatevidencedowehavethatendogenoustransforminggenesareinvolvedinhumancancer?AIIoftheretroviraloncogenesdiscoveredthusfarhavecellularhomologues(proto-oncogenes)thatarethoughttobeinvolvedinnormalcellularfunction(seeChapter5).Ifthesenormalgenesaretocausecancertheirstructureortheirexpressionmustbeperturbed.Examplesofsuchchangesincludethefollowing:l.Pointmutationswithinthegene2.Geneticrearrangementswithinthecodingsequenceofthegene3.Geneticrearrangementsoutsidethecodingregion4.Amplificationand/oroverexpressionofthegeneEachofthesemechanismsresultsinthe"activation"ofoneoranotherofthecellularproto-oncogenesthathasbeenassociatedexperimentallywithhumancancer.Anadditionalmechanismforwhichthereispreliminaryexperimentalevidenceis.5.Deletionofpossible"anti-oncogenes"PointMutations,rasGeneandHumanNeoplasiaThemostnotableclassofoncogenesactivatedbypointmutationistherasfamily(Table6.l).Thefirstactivatedhumanoncogenewasisolatedfromahumanbladdercarcinomacellline,T24,byseveralresearchersin1982.ShihandWeinberginitiallyreportedthatatransformingprinciplepresentintheDNAofT24cellsbycouldbetransferredintoN!H373cellsbyDNAtransfection(Fig.6.l).Specifically,genomicDNAisolatedfromthebladdercarcinomacelllinewouldtrans-TABLE6.1Examplesofrasmutationsthattransforminthe3T3focusformationassay.ras,AlleleEmaxSourceofalleleCodonsFocusformation125961c-H-rasNormalhumanGGCGCCCAGNoGlyAlaGluc-H-rasBladdercarcinomalineGTCGCCCAGYesValAlaGlac-K-rasNormalhumanGGTGCACAANoGlyAlaGluc-K-rasLungcarcinomaTGTGCACAAYesLysAlaGluN-rasNormalHumanGGTGCTAAANoGlyAlaGluN-rasNeuroblastomalineGGTGCTAAAYesGlyAlaLysVOCABULARYl.double-strandedDNAviruses雙鏈DNA病毒2.diploidRNAviruses二倍體RNA病毒3.retroviral反轉錄病毒的4.neoplasia瘤5.papillomaviruses乳頭瘤病毒6.urogenital泌尿生殖的7.herpesviruses皰疹病毒8.Burkitt'slymphomaz伯基特淋巴瘤9.nasopharyngeal鼻咽的10.hepatitis肝炎ll.transformingsequences轉化順序12.polyomaviruses多瘤病毒13.adenoviruses腺病毒14.invivo[拉〕在活體內15.oncogenes腫瘤基因16.rodent嚙齒類17.celluartransformation細胞轉化(作用)18.nostsequences宿主序列19.lifecycle生命周期20.provirus原病毒、前病毒21.integrateinto整合到……中22.cellularsequences細胞順序(序列)23.genome基因組24.oncogenesis腫瘤形成，發生25.oncornaviruses致腫瘤RNA病毒26.proto-oncogene原癌基因27.counterpart副本，負本28.