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Each has led to the discovery of a corre_sponding proto-oncogene that is present in normal animal cells.Figure2O-27Cancer-criticalmutationsfall into two readilydistinguishablecategories,dominant and recessive.Inthis diagram,activatingmutationsarerepresentedby solid red boxes,inactivatingmutationsby hollowredboxes.(A)Oncogenesact in a dominantmanner:a gain-of-functionmutationin asinglecopyof the cancer-criticalgenecan drive a celltoward cancer.(B)Mutationsin tumor suppressorgenes,on the other hand,generallyact in arecessivemanner:the function of bothallelesof the cancer-criticalgene mustbelost to drive a celltoward cancer.Althoughin this diagramthe secondalleleof the tumor suppressorgeneisinactivatedby mutation,it is ofteninactivatedinsteadby lossof the secondchromosome.Not shown is the fact thatmutationof sometumor suppressorgenescan havean effectevenwhen onlyone of the two genecopiesis damaged.'raqloueeuo oo]rouo dn alrd^aql leql os 'MoJbol anurluo)pue slurPrlsarIllensnasaqlpre6arsrp' l s e r l u o )u r ' s l l a r) a ) u e );uorlrqrqull)eluo),,sPuMoul uouourouorloe-slla) raqlo ql!M sl)eluo),(q palrqrquraq ol pue'Llsrpaql qrlMl)eluo) uo puadapol suraosuor1erallo.rd:slla)Jo ralel ol6urse qllm qslpaql paladre>aneqIaql aruo 6ur1era1;o.rdools slla)lPLrrroulsow'arnlln) lla) u!uolllqrqurl)eluo) lo ssol 6J-97 arn6r1'VNU slunourea6.re;saleu.rlosnr^ aqt asne)aqpa:npordrenoI;1ear6os;esruralordrr5-neql'(69-9 arn611aes)aseurl uralo.rd>r;r:ads-aurso.rr(lepue anrg>erad,(qse pale;n6arunrl 6ulleLl'(urvtoqs ulalordaqt e)uanbaslou)Jopr)e ouil.!e aql Jalleleql suorlelnuJsureluo)rJS-i'uorlrppeur .'rs-l Jo lnoperr;dsuaaqa^eqrr5 rplnlla)ur luasardsuo.ltutaql'pa^uap uaaqseql! q)!qMr-uol1aue6o>uo-otord)/S.relnlla)aqt pueeua6oruo )JS-ztaql uaa/vrlaqdrqsuorle;araql (B)'suorl)un;6urssrr-uaqt sar;ddnst-:'ttgm'srun nd 1aq6urturolsuerluou'a^rl)aJapuoue qlr^^pal)a]u!{;snoauel;nwrss! leqr lle) e ur {;uose;rrlredsnor])a;Uralereuabue) snrn6urluio;suer1oql aro;araqf'aua6oruo6uru.r.ro;suer1eq] setrnbtesnlrno.rlalaql uaqMtso;,(;lredro,{lloqMaresaua6'sasnr^orlarleIA asaqlJo arourro auorrua6oruoroqto ul'(uretordor,{;6ado;anuaaql sarnpordqlrqM)^ufpue'(euoua6lsoq aq] olur au..rosourotrl)lerl aqt 6ulterbatulur pa^lo^uraur,(zuauP pue aselou)suellasle^alsa)npoJor.l)!r.lm)/od'(suralold prsder aqt atetaua6o] paleal) sr1eq1urelord,{1ode sarnpordqrtqm)6o9 :ap,(r a;r;;elrrrfueurp.roaql ro4parrnbatseua6leltAaa.lqleqlpaurelarseql! leql ur seua6oruor{rerleql sasnrnorlaraql 6uoue lpnsnunsrsnr^ euro)lessnou'(snltAetualnalauunu) snlrloJlar;errdIl arou e;oreqr qrlMpareduor seeuroua6ler^ aqtaqf (V)'snr^ puro)res1ouorlezrue6rosnog aql ro arnl)nlls aq1 97-97 arn6r1q s r pe J n l l n ) - a n s s)rrl l s e l our r.unrpauqyrrorb'(62-02 arn-31g)aleraglord Laql sBre^{EIuodn Je,(eldn apd pue amqns aq] uI sllac peuroJ-sueJlun eql ^aoJSlnoduoloJ eql SuIruJoJslleJ paruJoJsueJ]aq] :uopBJeJIIoJdIIacaql pesEeleJleql eueSpeppe uE 8ul{.ue3eqlJo aruos tuoquo sloJluosIIaJIPrsos'lla3 elSursp ruo4 pelEulSlro ]eqt sllec auolJ B sI duolor qJeA <V913> 'uopJo-BruJoJsnBJl auoSJapun e^eq o] rc pau)otsuaq eq ot prcs aJP^eql 'sarlradordsnoJacueJ deldsrp saruoloc qJns SuIurJoJsllac eql asneJeq ireadde 01 ulSeqslleJ SurleJaJrloJd.|{.lleuuouqEJo saluolol IIEIus 'auaSoJuo uP sulBluoJ slualu-3er1aqt go due;1 's11acpeJnllnJ aq] olul peJnpoJlul pue 'sluaur8e4 olul ueloJq'sllac Journl eq] tuo4 patJeJue slVNCI ,{ea,rslql uI auaSoouo uE }Ja}ap oJ'lJaJJae aJnpoJd o1qSnoua eq ueJ eueSosuo el8crlEruerp-urs p Jo uorlrppP aql 'uoseal slql Joc dcueuSqeur pJej\/\ol,{.u,,Vraql;o ued luaqla{E} lPql suor}BJellE 3l}aue3 ulEluoc Lpearp o} }q8noql eJE 'eJn}lnl uI d.lellu-lJepul elEreJrTordo1 palJales dlsnornard 'sllef, aseqJ 'slsPlqorqg asnou luo4pa^rJap sauq IIeJ pasn ^llPnsn r(aq] 'desseeql JoJ sllef, Jalsal sv 'seuq IIaJ sno-JecueJuou olq pecnpoJlur uaqM uortEJeJIIoJdpelloJluocun a{o^oJd plnoJ }eq}slleJ raruec uBrunq ur seruanbas vNC roJ paqcJBespue qf,EoJddElJeJIp alorue {oo} sJaq}o'sasnJIAoJlaJur sauaSocuoJoJ paqf,rees sreqJJEaseJeruos eIqA\seu-ouaDloJsaq)leesluelarJloaues eql uo pabta^uo)aAeHsauabo>ug(s)aua6oruotfilsl-:,€||eua6o:uo-o1oldrr5-r ua))rtl)uotlu Iu r e u J o po s e u r l6 u r p o r u eu o t b a .
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O B L A S T O M Ao c c a s i o n acle l l i n a c t i v a t e sone o{ its two good Rb genes\\,/ffiGo c c a s i o n acle l linactivatesone of its twonnnrlPAnonoc/\\Io c c a s i o n acle l lIi n a c t i v a t eist s o n l y Ig o o d R bg e n ec o p y IL;,4\.,/ l\the seconrl.oPY ot IRb is very rarelY Iinactivatedin theAsame line ,/iolcells /cellexcessivep r o l i f e r a t i o nl e a d i n gto retinoblastoma\'n*i'i':rfuih:'RESULNT OT U M O RE I T HI N H E R I T E DRESULMT O S TP E O P LWD E V E L OMP U L T I P LTEU M O R SMUTATIONI N B O T HE Y E SRESULTONLYABOLIT1 IN 3O,OOOPNEE E V E L OON O R M A LP E O P LDT U M O RI N O N EE Y EIung, breast, and bladder.
These more common cancers arise by a more complexseriesof genetic changesthan does retinoblastoma, and they make their appearance much later in life. But in all of them, it seems, Ioss of Rb function is frequently a major step in the progression toward malignancy.The Rb gene encodes the Rb protein, which is a universal regulator of thecell cycle present in almost all cells of the body (seeFigure 17-62).It acts as oneof the main brakes on progress through the cell-division cycle, and its loss canallow cells to enter the cell cycle inappropriately, as we discuss later'GenesCanAlsoBeldentifiedfrom StudiesofTumorSuppressorTumorsThe Rb story illustrates how rare hereditary cancer syndromes can be used touncover tumor Suppressorgenesthat are relevant to common sporadic cancers.However, only a few of the tumor Suppressorgenesnow known to be importanthave been discoveredin this way.A more direct approach to the identification oftumor suppressor genes have already been well characterized and many moreare known.TumorCanInactivateMechanismsBothGeneticand EpigeneticGenesSuppressorIt is the inactivation of tumor suppressor genesthat is dangerous.This inactivation can occur in many ways, with different combinations of mishaps converging to eliminate or cripple both gene copies.The first copy may, for example, belost by a small chromosomal deletion or inactivated by a point mutation.
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