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CASEREPORTOpenAccessAlargedenovo9p21.
3deletioninagirlaffectedbyastrocytomaandmultiplemelanomaSimonaFrigerio1,VittoriaDisciglio2,SiranoushManoukian3,BernardPeissel3,GabriellaDellaTorre1,AndreaMaurichi4,PaolaCollini5,BarbaraPasini3,6,GiacomoGotti7,AndreaFerrari7,LiciaRivoltini1,MauraMassimino7andMonicaRodolfo1*AbstractBackground:Associationofmelanoma,neuralsystemtumorsandgermlinemutationsatthe9p21regionintheCDKN2A,CDKN2BandCDKN2BASgeneshasbeenreportedinasmallnumberoffamiliesworldwideanddescribedasadiscretesyndromeinmelanomafamiliesregisteredasararedisease,themelanoma–astrocytomasyndrome.
Casepresentation:Weherestudiedtwoyoungpatientsdevelopingmelanomaafterradiotherapyforastrocytoma,bothreportinglackoffamilyhistoryformelanomaorneuralsystemtumorsatgeneticcounselling.
PatientAisagirltreatedforanaplasticastrocytomaat10yearsandformultiplemelanomasonthescalpassociatedtodysplasticnevitwoyearslater.
Hermonozygotictwinsistercarrieddysplasticneviandaslowgrowing,untreatedcerebrallesion.
DirectsequencinganalysisshowednoalterationsinmelanomasusceptibilitygenesincludingCDKN2A,CDK4,MC1RandMITForinTP53.
Bymicrosatelliteanalysis,multiplexligation-dependentprobeamplification,andarraycomparativegenomichybridizationadeletionincludingtheCDKN2A,CDKN2BandCDKN2BASgeneclusterwasdetectedinbothtwinsisters,encompassingalargeregionat9p21.
3andoccurringdenovoafterthelossofonepaternalallele.
PatientBisaboyof7yearswhentreatedforastrocytomathendevelopingmelanomaassociatedtocongenitalnevionthehead10yearslater:sequencingandmultiplexligation-dependentprobeamplificationrevealedanormalprofileoftheCDKN2A/CDKN2B/CDKN2BASregion.
Arraycomparativegenomichybridizationconfirmedtheabsenceofdeletionsat9p21.
3andfailedtorevealknownpathogeniccopynumbervariations.
Conclusions:BycomparisonwiththeothergermlinedeletionsattheCDKN2A,CDKN2BandCDKN2BASgeneclusterreportedinmelanomasusceptiblefamilies,thedeletiondetectedinthetwosistersispeculiarforitsdenovooriginandforitsextension,asitrepresentsthelargestconstitutivedeletionat9p21.
3regionidentifiedsofar.
Inaddition,thetwostudiedcasesaddtootherevidenceindicatingassociationofmelanomawithexposuretoionizingradiationandwithsecondneoplasmafterchildhoodcancer.
Melanomashouldbeconsideredinthemonitoringofpigmentedlesionsinyoungcancerpatients.
Keywords:Melanoma-astrocytomasyndrome,9p21.
3deletion,CDKN2A,CDKN2BAS,MLPA,Oligoarray-CGH*Correspondence:monica.
rodolfo@istitutotumori.
mi.
it1DepartmentofExperimentalOncologyandMolecularMedicine,FondazioneIRCCSIstitutoNazionaledeiTumori,viaVenezian1,Milan20133,ItalyFulllistofauthorinformationisavailableattheendofthearticle2014Frigerioetal.
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TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.
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Frigerioetal.
BMCMedicalGenetics2014,15:59http://www.
biomedcentral.
com/1471-2350/15/59BackgroundThecombinationofmelanomaandneuralsystemtu-mors(NST)wasdescribedinmelanomafamilieswherethediseasesoccurredindifferentfamilymembersorconcomitantly,andwasregisteredasararedisease,themelanoma-astrocytomasyndrome(OMIM155755).
ThreefamiliesfromFrance,UKandUSAshowingas-sociationofmelanoma,NSTandgermlinedeletionsofpartoroftheentireCDKN2Alocus,aswellasofCDKN2Bandthenon-codingCDKN2BASgenes,havebeendescribed[1-3].
Inotherstudies,familiespronetomelanomaandNSTlackeddeletionsinthe9p21region,althoughotheralteredlocicausingthesyndromehavenotbeenidentified[4-7].
MissensemutationsinCDKN2AgeneswerealsodescribedinoneFrenchandtwoItalianfamiliesreportingmelanomaassociatedwithmeningiomaandneuroblastomarespectively[8,9].
Theanalysisofothergeneslocatedinthisregion,suchasKLHL9andPTPRD,failedtoidentifyinheritedmutationsinmelan-omaandNSTkindreds[7,10].
WhilethegeneticbasisforNSTremainslargelyun-identified[11],severalgenesassociatedtomelanomapredispositionbesidesCDKN2Ahavebeenrecentlyidenti-fied[12].
Inarecentstudywegeneticallycharacterizedaseriesof21pediatricmelanomatreatedatourInstitute[13]:twocasesdevelopingmelanomaafterNSTwerestudiedfordeletionsatthe9p21region.
Herewereportthere-sultsoftheseanalyses.
CasepresentationWereportthecaseofafemaleItalianpatient(A)treatedforanaplasticastrocytoma(10yr)whodevelopedmultiplemelanomasonthescalpassociatedtodysplasticnevitwoyearslater(Figure1).
Inthefollowing8yearswhenshewasfollowedclinicallyatourInstitute,shedeveloped10melanomasonthehead,neck,trunkandleg.
Shealsode-velopedneurotechoma(8yr)andneurofibroma(18yr).
Atectalmesencephaliclesiongrowingalong10yearsandproducinghydrocephaluswasthefinalreasonforherdeath(20yr).
Hermonozygotictwinsister(TS)carrieddysplasticneviandaslowgrowing,untreatedcerebralle-sionatparietalcortex(22yr).
Thepedigreeprofileatgen-eticcounsellinglackedneoplasticdiseasesinthematernallineagewhileinthepaternallineageanuncleandhissonhadunspecifiedneoplasticdisease.
ThesequencinganalysisshowedwildtypesequencesforCDKN2A,CDK4,andMC1R;inaddition,TP53mu-tationsandtheMITFE318Kvariantidentifiedinfamilialmelanoma[14,15]werenotfound(datanotshown)(seeAdditionalfile1:Methods).
Theallelestatusofmicrosat-ellitemarkersintheCDKN2AgeneregionwasanalyzedinpatientA,herparentsandTS(seeAdditionalfile2:TableS1).
ForthemarkersD9S974,D9S942,D9S1748andD9S1749asinglepeakwasdetectedforthepatientandtheTS,whilefortheparentstwoalleleswithatleastonealleleofthesamesizewereshown.
Foreachmarker,theallelefoundhadthesamesizeofoneofthematernalallele(seeAdditionalfile3:FigureS1)indicatingtheoc-currenceofadeletionintheCDKN2Alocusinthepater-nalallele.
MultiplexLigation-dependentProbeAmplification(MLPA)showedhemizygosityofCDKN2A-CDKN2BgeneregionforpatientAandTS,andnormalprofilesfortheparents(seeAdditionalfile4:FigureS2),support-ingadenovoorigin.
Theanalysisofmetaphasechromo-somesfromEBV-immortalizedlymphocytesbyFISHhybridizationusingasprobetheC5cosmidspanningabout50kbofthechromosomalregionfromCDKN2AtoCDKN2Bgenesfurtherconfirmedthedeletioninthetwosisters(datanotshown).
Oligoarray-comparativegenomichybridization(aCGH)analysiswasperformedtoconfirmMLPAresultsandtobetterdefinethedeletionbreak-points.
TheanalysisofratioprofilesrevealedforpatientAandTSadeletionatthe9p21.
3chromosomalregionofapproximately2,135MbincludingpartoftheCDKN2BASFigure1HistopathologyoftheinitialbiopsyspecimensexcisedfromtheheadofpatientA.
Specimensfromtheheadneoplasmsofthepatientrevealingasuperficialspreadingmelanomawithepithelioidappearanceassociatedwithacompoundnevus(inset)(A)orintheabsenceofmelanocyticnevi(B).
Hematoxylinandeosin,magnification10*.
Frigerioetal.
BMCMedicalGenetics2014,15:59Page2of6http://www.
biomedcentral.
com/1471-2350/15/59Figure2SchematicrepresentationofthedeletionidentifiedinpatientAandofgermlinedeletionsatthe9p21.
3regionreportedinotherstudies.
A.
Array-CGH400Kratioprofile:ontheleft,thechromosomeideogram,ontheright,thelog2ratioofchromosome9probesplottedasafunctionofchromosomalposition.
ProbeswithavaluezerorepresentequalfluorescenceintensityratiobetweensampleandreferenceDNAs;eachfilledrectanglerepresentsasingleprobespottedonthearray.
Copynumberlossesshifttheratiotonegativelogratiovalues.
Inthelowerpart,thedeletedregionat9p21.
3detectedinpatientAisshowninredandthedeletedgenesarerepresentedaccordingtoUCSCGenomeBrowser(NCBIbuild37,hg19).
Thedeletedregionspansbetweenoligomersat19,934,142Mb(A_18_P26451569,firstdeleted)and22,069,983Mb(A_16_P18578628,lastdeleted),flankedbyoligomersat19,927,491Mb(A_16_P18573439,firstpresent)and22,086,798Mb(A_16_P18578677,lastpresent).
NoCNVsaredetectedforpatientBinthesameregion.
B.
Representationofthedeletionspreviouslyreportedinmelanoma-NST(ME-NST)andinmelanoma(ME)kindreds,inblueandgreylinesrespectively,incomparisontothedeletiondetectedinpatientA.
ThestatusofmicrosatellitemarkersandofgenescomprisedintheregionasderivedfromMLPAisshown.
Thestartnucleotidepositionformicrosatellitesandgenesisindicated(UCSCGenomeBrowser)[16-18].
Frigerioetal.
BMCMedicalGenetics2014,15:59Page3of6http://www.
biomedcentral.
com/1471-2350/15/59gene,CDKN2B,CDKN2A,MTAP,MIR31,theIFNAgenecluster,KLHL9,IFNW1,IFNB1,PTPLAD2,FOCAD,MIR491,SNORA30,MLLT3,MIR4473andMIR4474(Figure2A).
Thesecondcasestudied,patientB,isaboydevelopingmelanomaassociatedtocongenitalnevionthehead(17yr)afterastrocytoma(7yr).
Fiveyearslaterhedevel-opedfatalpleuricrhabdomyosarcoma.
Hispedigreelackedneoplasticdiseases.
NoalterationswererevealedbysequenceanalysisinCDKN2Ageneexceptforthers3814960andrs11515variantsinthe3′UTRand5′UTRregions,whicharerathercommonsinglenucleotidepoly-morphisms(SNPs)inmelanomapatients[19].
Inaddition,hecarriedwildtypeCDK4,MC1RandMITFgenes,andanormalprofileoftheCDKN2A-CDKN2BregionwasshownbyMLPA.
aCGHanalysisshowedanormalratioprofileatthe9p21.
3region(Figure2A)andrevealedcopynumbergainson4p14and6q24.
3ofuncertainclinicalsignificance,whichdeservefurtherstudiesandanalysesinotherpatientswithsimilardiseases(seeAdditionalfile5:TableS2).
ConclusionsGermlinemutationsatCDKN2Alocusaregenerallyinheritedfoundermutationshavingacommonancestralorigin,whiledenovomutationsappeartobeexceedinglyrareevents[20],thusmarkingapeculiarityinthegeneticofpatientA.
Althoughthepreciseendpointsofthedele-tionwerenotdeterminedhere,byaCGHitwasshowntospanfrom19,934,142to22,069,983Mb,thusbeinglargerthanthosepreviouslymappedbyPasmant[3].
Infact,inadditiontotheCDKN2A/CDKN2B/CDKN2BASgenecluster,thedeletionextendsinthetelomericendtocom-prisealargeregionuptotheMLLT3gene.
SimilarlytotheotherdeletionsdetectedinassociationwithmelanomaandNST,thedeletedregionincludespartoftheCDKN2BASgene,whichonthecontraryisnotalwaysincludedinthedeletionsoccurringinmelan-omakindredslackingNST,asschematizedinFigure2B.
CDKN2BASgene,orANRIL(antisensenon-codingRNAintheINK4locus),consistsof19exonsspanningare-gionof126.
3kblocatedwithintheCDKN2B-CDKN2Agenecluster,andistranscribedintheantisenseorientationinalongnon-codingRNAinvolvedinepigeneticsilencingofCDKN2B-CDKN2Alocusbypolycombrepressivecom-plexes[21].
Genome-wideassociationstudieshaveidenti-fiedSNPsinCDKN2BASassociatedwithsusceptibilitytoNSTaswellastomelanoma[22,23];interestingly,CDKN2BAShasbeenidentifiedasarisklocusalsoforothercancersanddiseases[24].
Amongtheothergenescomprisedinthedeletedregion,FOCADhasbeenshowndeletedingliomatumors[25].
Furthermore,inpatientB,CGHanalysisshowedcopynumbergainson4p14and6q24.
3chromosomalregionsinvolvingTCF25andKLF3genesrespectively,whichencodefortranscriptionfactors,representingpotentialcandidatesforfurtherstudies.
Infact,TCF25,hasbeeninvolvedinembryonicdevelopmentexpressedinbrain[26],andKLF3,hasbeenreportedtoshowrearrangementsindifferentcancertypes[27].
Ourstudyshowsthat9p21.
3deletionisneitherneces-sarynorsufficientfortheNST-melanomasyndrome.
Ofnote,bothpatientsdevelopedmelanomaontheirheadafterradiotherapyforastrocytoma,thusaddingtootherevidencesuggestingassociationofmelanomawithexpos-uretoionizingradiation[28-32];inaddition,theTSofpa-tientA,whowasnottreatedforNST,didnotdevelopmelanoma,althoughshecarriedanidentical9p21.
3dele-tion(seeAdditionalfile6:FigureS3).
Itresultsthatyoungcancerpatientstreatedwithradiotherapyshouldbecon-sideredatriskfordevelopingmelanomaandtheirpig-mentedlesionsshouldbecarefullymonitoredbyexpertclinicians.
Infact,althoughmelanomaisararediseaseinthehealthychildhoodpopulation,itoccursmorefre-quentlyassecondmalignantneoplasmafterchildhoodcancer[33]andshouldbecloselymonitoredbyregularlyscreeninthefollow-upofsurvivors,whichhaveanap-proximate2.
5-foldincreasedriskofmelanoma[34].
Fur-thermore,childrenwithgeneticsyndromesmayhaveuniquepathophysiologiesthatnecessitatecarefulevalu-ationandfollow-upofskinalterations,sinceoftenderma-tologistsfindunusualandatypicalcorrespondencesbetweenclinicanddermoscopicparametersandthehisto-logicalones[35].
Amultifacetedapproachincludingathoroughclinicalhistory,visualexaminationanddermo-scopicevaluationofsuspiciousskinlesionsisrecom-mendedtoincreasethesensitivityandspecificityfordiagnosingmelanomaintheseyoungpatients.
ConsentWritteninformedconsentwasobtainedfromthepatients'parentsforgeneticcounselling,DNAanalyses,scientificresearchandstudypurposesforallfamilymembers.
Theconsentformwasapprovedbythelocalethicalcommittee(ComitatoEticoCentraleIRCCSLombardia).
AcopyofthewrittenconsentisavailableforreviewbytheEditorofthisjournal.
AdditionalfilesAdditionalfile1:Methods.
Additionalfile2:TableS1.
Primersofthemicrosatellitemarkersusedinthestudy.
StartandendpositionsarereportedaccordingtoUCSCGenomeBrowser(NCBIBuild37,hg19).
Additionalfile3:FigureS1.
MicrosatelliteanalysisrevealinglossofthepaternalalleleinpatientAandTS.
HomozygosityorhemizygosityatmicrosatellitelociwasanalyzedbyPCRandamplificationproductsanalyzedwiththeABIPrismPeakScannerSoftware.
Additionalfile4:FigureS2.
ResultsofMLPAofthe9pregioninpatientA,TSandparents.
ResultsobtainedwithMLPAarraysforthe9p21regionorderedaccordingtothegenomiclocationoftheprobes.
Frigerioetal.
BMCMedicalGenetics2014,15:59Page4of6http://www.
biomedcentral.
com/1471-2350/15/59Genedosagequotientsforthe41probesandrelativeIDnumbersareshown,forpatientAandTSinfullbars,andforparentsinemptybars.
ThedeletiondetectedinthetwosistersextendsfromCDKN2BtoMLLT3genes,andincludesCDKN2A,MTAP,IFNA1,KLH9,IFNW1,andIFNB1genes;incontrast,ELAV2andTEKcentromerictoCDKN2BandGLDCandDOCK8telomerictoMLLT3showednormalgenedosagequotientsindicatingretentionofbothgenecopies.
Additionalfile5:TableS2.
ListofchromosomalaberrationsdetectedbyaCGH(400K)inpatientBnotreportedintheDatabaseofGenomicVariants(http://dgv.
tcag.
ca/dgv/app/homeref=GRCh37/hg19).
CNVsinnoncodingregionsweredetectedon7p12.
3,7q11.
22,19q13.
11chromosomalregions.
Alargeregionon14q11.
2containsgenespoorlycharacterizefunctionally.
CNVson4p14and16q24.
3involvegenesofpotentialinterestsincetheyhavebeeninvolvedintheregulationofcellgrowthanddeath.
Additionalfile6:FigureS3.
Resultsofarray-CGHofthe9p21.
3regioninpatientAandhertwinsister.
aCGHanalysisshowedanidentical9p21.
3deletionof~2,135Mb.
AbbreviationsNST:Neuralsystemtumor;MLPA:Multiplexligation-dependentprobeamplification;TS:Twinsister;SNP:Singlenucleotidepolymorphism;aCGH:arrayComparativeGenomicHybridization;CNV:Copynumbervariation.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsSFcarriedoutthePCRamplifications,sequencingstudies,MLPAandmicrosatelliteanalysesandhelpedtodraftthemanuscript.
VDcarriedoutarray-CGH,theanalysisoftheresultsandhelpedtowritethefinalmanuscript.
AMandPCcarriedouttheclinicalandthepathologicanalysesandhelpedtodraftthemanuscript.
SM,BPandPPthegeneticcounsellingandhelpedtodraftthemanuscript.
GDTdesignedthestudyandthegeneticanalysis.
GG,AFandMMconceivedofthestudy,andparticipatedinitsdesignandcoordinationandhelpedtodraftthemanuscript.
MRandLRdesignedthestudy,definedtheresultsandfinalizedthemanuscript.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgementsThisworkwassupportedbyagrantfromtheMinistryofHealthandbytheItalianAssociationforCancerResearch(AIRC).
Authordetails1DepartmentofExperimentalOncologyandMolecularMedicine,FondazioneIRCCSIstitutoNazionaledeiTumori,viaVenezian1,Milan20133,Italy.
2DepartmentofExperimentalOncologyandMolecularMedicine,FunctionalGenomicsandBioinformaticsCoreFacility,FondazioneIRCCSIstitutoNazionaledeiTumori,viaVenezian1,Milan20133,Italy.
3UnitofMedicalGenetics,DepartmentofPreventiveandPredictiveMedicine,FondazioneIRCCSIstitutoNazionaledeiTumori,Milan,Italy.
4UnitofMelanomaandSarcoma,DepartmentofSurgery,FondazioneIRCCSIstitutoNazionaledeiTumori,Milan,Italy.
5DepartmentofPathology,FondazioneIRCCSIstitutoNazionaledeiTumori,Milan,Italy.
6Currentaddress:DepartmentofMedicalScience,UniversityofTurin,Turin,Italy.
7PediatricUnit,FondazioneIRCCSIstitutoNazionaledeiTumori,Milan,Italy.
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