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Thesecond copy is commonly eliminated by a less specific and more probableFigure20-!!0The geneticmechanismsIn thethat causeretinoblastoma.lbrm,all cellsin the body lackhereditaryone of the normaltwo functionalcopiesgene,andof the Rbtumor suPpressortumorsoccurwherethe remainingcopyby a somaticeventis lostor inactivated(eithermutationor epigeneticsilencing).form,all cellsIn the nonl'rereditaryinitiallycontaintwo functionalcopiesofthe gene,and the tumor arisesbecauseboth copiesarelostor inactivatedof two somaticthroughthr:coincidenceeventsin one lineof cells.1236Chapter20:CancerHEALTHYC E L LW I T HO N L YO N EN O R M A LR b G E N EC O P YP O S S I B LWEA Y SO F E L I M I N A T I NNGO R M A LR b G E N Enondisjunction chromosomecausesl o s s t, h e nchromosome chromosomelossduplicationmitoticrecombinationgeneconverstonpointmutationmechanism: the chromosome carrying the remaining normal copy may be lostfrom- the cell through errors in chromosome segregition, or the normal genemay be replaced by a mutant version through either mitotic recombination or agene conversion event.Figure 20-31 summarizes the range of possible ways to lose the remaininggood copy of a tumor suppressor gene through DNA sequence changes, usingthe Rb gene as an example.
It is important to note that, except forihe poinlmutation mechanism illustrated at the far right, these pathways all produce cellsthat carry only a single type of DNA sequence in the ihromoio-aregion containing their /ib genes-a sequencethat is identical to the sequencein the original mutant chromosome.As discussed in chapter 4, normal human genetic variation makes each ofour maternal and paternal chromosome sets distinguishably different. on average,.human DNA sequences differ-that is, we are heterozygous-at roughlyone in every thousand nucleotides.
\Mhere a large segment of one chromosomihas been either lost or converted to the DNA sequence in its homologous chromosome, as in Figure 20-31, there is a lossof heterozygosity (LoH): only one version of each variable DNA sequence in that neighborhood remains. Millions ofcommon sites of heterozygosity in the human genome have been mapped aspart of the Human Genome project: each of these sites is characterizedby a specific DNA sequence that is known to be polymorphic-that is, to occur commonly in two or more slightly different versions in the human population.
Givena sample of tumor DNA, one can check which of the versio.rsbf ihese polymorphic sequencesare present. The same can be done with a sample of nruA fromnoncancerous tissue from the same patient, for comparison. A loss of heterozygosity throughout a region of the genome containing one or more polymorphicsites,or loss of a genetic marker sequencethat is seen in the non-cancerous control DNA, can point the way toward a chromosomal region that contains a relevant tumor suppressor gene. However, because of their genetic instability, cancer cells often exhibit a loss of heterogeneity for -any diff".ent chromosomalregions.
Therefore the detection of tumor suppressor genes by this approachgenerally requires the subtraction of a large amount of rindom noise.Epigenetic changes provide another important way to permanently inactivate a tumor suppressorgene. Most commonly, the gene may become packagedinto heterochromatin and the c nucleotides in cpG sequencesin its promolermay become methylated in a heritable manner (seeFigure 20-12).Theie mechanisms can irreversibly silence the gene in a cell and in all of its progeny. Givena catalog of possible tumor suppressorgenes,it is relatively easyto test their promoters for abnormal amounts of DNA methylation. Studies of thisRpe suggestthat epigenetic gene silencing is a frequent event in tumor progression, and epigenetic mechanisms are now thought to help inactivate seneril different tumorsuppressor genes in most human cancers (Figure ZO_JZ).Figure20-31 Six ways of losing theremaininggood copy of a tumorsuppressorgenethrough changesinDNA sequences.A cell that is defectiveinonly one of its two copiesof a tumorgene-for example,thesuppressorRbgene-usually behavesasa normal,healthycell;the diagramsbelowshowhow this cell may losethe functionof theothergenecopyaswell and therebyprogresstoward cancer.A seventhpossibility,frequentlyencounteredwithsometumor suppressors,is that the genemay be silencedby an epigeneticchange,withoutalterationof the DNAsequence,as illustratedin Figure20-32.(AfterWK.
Caveneeet al.,Nature305:779-784,1983.With permissionfromMacmillanPublishersLtd.)GENESFINDINGTHECANCER-CRITICALFigure20-32:The pathwaysleading tolossof tumon suppressorgene functionin cancerinvolve both genetic andinepigeneticchanges.As discussedChapter4, the packagingof a geneintocondensedchromatincan preventitsin a way that is inheritedexpressionwhen a celldivides(seeFigure4-52).Asthe changesthat silencetumorindicated,genescan occurin anyorder.suppressormutationtumorsuppressorh e r i t a b l eg e n e s i l e n c i n gi nc o n d e n s e dc h r o m a t i nqeneJ!-+++ORI= g e n e t i cc h a n g eI= e p i g e n e t i cc h a n g e&CANCERr*imORpa,mGenesMutatedin CancerCanBeMadeOveractivein ManyWaysIn the case of a proto-oncogenes it is gene activation that leads toward cancer.Figure 20-33 summarizes the types of accidents that can convert a proto-oncogene into an oncogene. (1) A small change in DNA sequence such as a pointmutation or deletion may produce a hyperactive protein when it occurs withina protein-coding sequence, or lead to protein overproduction when it occurswilfrin a regulatory region for that gene.
(2) Gene amplification events, such asproduced.Specific rypes of abnormality are characteristic of particular genes and ofthe responses to particular carcinogens. For example, 90% of the skin tumorsproto-oncogeneDELTTION.]ORPOINfINMUTATIONcoDrNGstQurruce:REGULATORYMUTATIONIIVDNARNA Ehyperactivep r o t e i nm a d e i nn o r m a la m o u n t srlIIVIflI-:Enormal proteingreatlyoverproducedn o r m a lp r o t e i ng r e a t l yoverproducedinto an oncogene'Figure20-33 The types of accidentsthat can make a proto-oncogeneoveractiveand convert it1238Chapter20:Cancerhomogeneouss t a i n i n gr e g i o nr + ,ri,;'l'Jc h r o m o s o m eA(c)a b e r r a n tr e p l i c a t i o n/#*"#11':chromosomeBFigure20-34 Chromosomalchangesin cancercellsresultingfrom geneamplification.Intheseexamples,the numbersof copiesof a Mycproto-oncogenehavebeenamplified.Rmplificationof oncogenesis commonin carcinomasand is oftenvisibleasa curiouschangein the karyotype:the cellis seento containadditionalpairsof miniaturechromosomes-socalleddoubleminutechromosomes-orto havea homogeneouslystainingregion interpolatedin the normal bandingpatternof one of its regularchromosomes.Boththeseaberrationsconsiitoi massivelyamplifiednumbersof copiesof asmallsegmentof the genome.Thechromosomesarestainedwith a redfluorescentdye,whilethe multiplecopiesof theMyc Aeneare detectedby ln sltuhybridizationwith a yellow fluorescentprobe.(A) Karyotypeof a cell in which theMyc9enecoplesarepresentasdoubleminutechromosomes(pairedyeltowspecks).(B)Karyotypeof a cellin whichthe multipleMyc genecopiesappearas a homogeneouslystaining region(yettow)interpolatedin oneof the regularchromosomes.(ordinarysingle-copyMyc genescan be detected as tinyyellowdofselsewherein the genome.)(Cischematicof how geneamplificationoccurs'lt is thoughtthat a rare,abnormalDNAreplicationeventproducesa chromosomewith extracopiesofone chromosomalregion,as shown.The repairof this structurereleasesDNAcirclesthat can replicateto form longt a n d e m l y r e p e a t e d s e q u e n c e s , p r o d u c i n g d o u b l e m i n u t e c h r o mAo ss tohme er ess.
u l t o f a s e c o n d r a r e e v e n t , t h e D N Afrom one of thesechromosomescan becomeintegratedinto a new siteon a normalchromosometo produceahomogeneouslystainingregion.Otherpathwayscan alsoamplifygenes,suchasthat describedlaterin Figure20-41.(A and B,courtesyof DeniseSheer.)evoked in mice by painting the skin with the tumor initiator dimethylbenz[a]anthracene (DMBA) have an A-to-T alteration at exactly the same site ina mutant Ras gene; presumably, of the many mutations caused by DMBA,onlythose at this site efficiently stimulate skin ceils to form a tumor.1239GAELN E SFINDINGT H EC A N C E R .
C R I T I Coverproduction appears to be due to a change in a regulatory element that actson the gene. For example, a chromosomal translocation can inappropriatelybring powerful gene regulatory sequences next to the Myc protein-codingsequence, so as to produce unusually large amounts of Myc mRNA. Thus, inBurkitt's lymphoma a translocation brings the Myc gene under the control ofsequencesthat normally drive the expression of antibody genes in B lymphoc1tes.As a result, the mutant B cells tend to proliferate excessivelyand form atumor.
Similar specific chromosome translocations are common in other lymphomas and leukemias.GenesContinuesTheHuntfor Cancer-criticalThe sequencing of the human genome has opened up new avenues for the systematic discovery of cancer-critical genes. It is now possible, in principle, toexamine every one of the approximately 25,000human genes in a given cancercell line, or in samples of tissue from a set of casesof cancer of a given type, looking for potentially significant abnormalities, using automated analysis of eithertheir genomic DNA or the mRNAs the cells produce. By analyzing substantialnumbers of different cancers, it should be possible eventually to identify all thegenesthat are commonly altered in human cancer.Although enormously costly,large-scaleDNA sequencing efforts have already begun to identify new humanoncogenes.One example is the finding that a hyperactive form of the Raf proteinkinase (discussedin Chapter 15) is present in a high percentage of melanomasand, at lower frequency, in other cancers.Straightforward DNA sequencing is not the only way to tackle the problem,however, and there are other powerful new methods for identifying new oncogenes and tumor suppressor genes that seem more efficient.
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