SnapShot:GeneticMouseModelsofCancerLarsZender,JohannesZuber,andScottW.LoweColdSpringHarborLaboratoryandHowardHughesMedicalInstitute,ColdSpringHarbor,NY11724,USAGeneGeneticApproachPrimaryTumorTypesCooperativityModelsClinicalSignificancep53TumorSuppressorTrp53mousegermlineknockout.Trp53−/−homozygous:100%tumorpenetranceat?4.5months.Typicaltumors:Tcelllymphoma(>60%);softtissuesarcoma(?25%);osteosar-coma,braintumors,teratoma(together<15%);carcinomasrarelyobserved.Trp53+/−heterozygous:50%tumorpenetranceat17months.Typicaltumors:Tcelllymphoma(?30%);softtissuesarcoma(?30%);osteosarcoma(?30%);morecarcinomasthanTrp53−/−mice.OncogeniccooperativityobservedbetweenTrp53−/−andotherlesionssuchasRb−/−orEµ-Myc.CarcinogenesisinducedbydifferentgenotoxicagentsorirradiationisacceleratedinTrp53-deficientmice.MutationsinTP53foundinmorethan50%ofallhumantumors.Trp53pointmutationknockinmiceexpressTrp53(R172H)orTrp53(R270H)fromtheendog-enouslocus.TumorspectradifferfromgermlineTrp53knockoutmicewithmorecarcinomas,Bcelllymphomas,endothelialtumors.Inmice,Trp53(R172H)andKras(G12D)cooperatetopromotechromosomalinstabilityandmetastaticpancreaticductaladenocarcinoma.Li-FraumenisyndromepatientshaveTP53pointmutationsratherthandeletions,soknockinmicearebettermodelsofthisdisease.ConditionalTrp53knock-outmicecarryloxPsitesinintrons1and10oftheTrp53locus.Homozygousmicearenottumorprone.WhencrossedwithmiceexpressingCreinthegermline,wild-typeTrp53alleleisexcisedandmicedevelopthesametumorspectrumasTrp53germlineknockoutmice.ThesemicedevelopbreastcancerwhencrossedwithBrca2conditionalknockoutmiceandK14-Cremice.WhencrossedwithRb1loxP/loxPmice,small-celllungcancerresultsaftertreatmentwithAdeno-Creanddeletionofthetwotumorsuppressorgenes.BreastcanceristhesecondmostfrequentcauseofdeathamongUSwomen.1in27womendiesofbreastcancer.Small-celllungcancerac-countsfor?20%ofalllungcancers.Ink4a/ArfTumorSuppressorsInk4a/Arfgermlineknockoutmicecarryadeletionofexon2/3oftheInk4a/Arf(Cdkn2a)locuseliminatingbothp16(Ink4a)andp...
