FibroblastGrowthFactorreceptor3MutationsinEpidermalNeviand成纤维细胞生长因子受体3基因突变与表皮痣

FibroblastGrowthFactorreceptor3MutationsinEpidermalNeviandAssociatedLowGradelBladderTumors.

HernandezS,TollAetal

JID(2007,July),Volume127

INTRODUCTIONEpidermalNeviarebenignhamartomasinchildhood.TheypresentasverrucoidscalyplaquesfollowingBlaschko’slines.Histologicallythesetumorsaresimilartoseborrheickeratosis(SK).

FGFR3mutationsarefoundinSK(39%incidenceinastudy)(Hafner,2007)and86%ofadenoidseborrheickeratosis,butthehighestincidenceisfoundinUrothelialCarcinomasandarethenassociatedwithlowgradetumors(goodprognosis).

EpidermalnevusSeborrheickeratosisAcanthosisNigricansFGFR3DNAmutationsarefoundinSkeletaldysplasias(exons7,10,15),andtheresultantconstitutivekinaseactivitycorrelateswithdiseaseseverity.Theauthorsfoundacaseofa41yearoldpatientwithacongenitalwidespreadnonepidermolytickeratinocyticEpidermalNevi(inadditionto3otherliteraturereports).Patienthadahistoryoflowgradeurothelialcarcinomaatage19.BasedonthreepreviousreportsofassociatedUCandENandthehistologicalresemblanceswithSK,theauthorshypothesizethatENmightbecausedbyFGFR3mutations.

TosearchforFGFR3mutationsinepidermalnevusGoalMATERIALSANDMETHODS25ENshowingonhistologyacommonpatterns(papillomatosis,acanthosis,hyperkeratosis)oracrokeratosisverruciformisorSKpattern.25patientsMicrodissectionDNAextractionPCRamplificationofFGF3Rexons7,10and15

RESULTSNostatisticaldifferenceingender,ageatdiagnosis,location,numberofEN,histologicalsubtype.6patients:R248Cmutationinexon7foundExons10and15normalinallcasesThetwospecimensofnormalskinshowedFGFR3wildtypesequences

FGFR3waspositivelystaining(althoughweakly)onimmunohistochemistryinthebasalcelllayerin2/6FGFR3mutatedsamplesand9/13FGFR3wildtypesamples.Thisissimilartotheweakdetectioninthenormalepidermis

DISCUSSIONMutationsofFGFR3occurfrequentlyinEN.Mutationsareabsentinnormalskin=mosaicism.MosaicisminacnehasalsobeendescribedforFGFR2.

AtthesametimeHafneretalfound:-41%(16/39)lesionsofFGFR3mutationsinEN(11outof33patients)-38/39specimensshowedtheR248Csubstitution.Intheremainingcasetwomutations(G372CandG382R)weredetectedonexon10.-4specimensofperilesionalskinshowedFGFR3wildtype.InanothertypeleucocyteDNAalsodemonstratedFGFR3wildtype.WhileFGFR3maycontributetothedevelopmentofENandUC,othergenesmaycontribute:-PIK3CAwhichisassociatedwithlowgradeUC-PTCHandTSC1whicharealteredinskinandbladdertumors.COMMENTARY(Hafneretal.)(1572-1573)FGFR3mutationsaredescribedinSyndromesprovokingskeletaldysplasiaandacanthosisnigricans(AN)suchas,thanatophorisdysplasia,SADDANandCrouzonsyndrome.Saddansyndromeisassociatedwiththedevelopmentofacanthosisnigricans.AN,ENandSKsharepapillomatosis,acanthosisandhyperkeratosis(…eventhoughonlyANisintertriginous).AchondroplasiaalsoaskeletaldysplasiasyndromeischaracterisedbyG1144Amutation,andthismutationhasnotbeendetectedinSKandEN,whichhypothesizesthatFGFR3isimportantinthedevelopmentofAN.Furtherstudiesareneededthough.SomaticmutationsalsodescribedinUCandMultiplemyeloma

TransgenismiceFGFR3(S249C)mutantdevelopverrucousskinlesionssimilartoSK(Logieetal,2005).TheauthorswentontoidentifyactivatingFGFR3mutationsin39%ofSklesions.

MechanismscausingFGFR3mutationareunknownbuttheR248CmutationappearstobeahotspotinENasitwasfoundbythetwostudiespublishedinthecurrentissue.TheR248CmutationisaCtoTtransitionintheDNAandmightbecausedbysunlight.SunlighthasbeenshowntobeanindependentriskfactorforthedevelopmentofSK(notinEN).AberrantFGFR3signallingenhancesproliferation,resistancetoapoptosis,orsenescence.OthermutationsdownstreamcouldaccountfortheotherUCandacanthoticskinlesions:-PI-3K/PTEN/AktorRas/Raf/MAPKpathways-PTCHandTSC1genes

Othermutationsstillcouldaccountforthehistologicsubtypeofthesegenes.ForexampleFGFR3mutationsalonecouldn’texplainwhyacanthosisnigricansasopposedtoENandSKareintheintertriginousareas.

FGFR3isabenignmutationasUC,AN,SKandENallhaveabenignbehaviour.Controlledandlimitedgrowth.

Conclusionofthecommentary[Several]specificsmall