外顯子組測序發(fā)現(xiàn)胰腺神經(jīng)內(nèi)分泌腫瘤(PanNETs)中DAXX-ATRX,MEN1

1/1外顯子組測序發(fā)現(xiàn)胰腺神經(jīng)內(nèi)分泌腫瘤(PanNETs)中DAXX_ATRX,MEN1外顯子組測序胃泌瘤素

NIHPublicAccessAuthorManuscriptScience.Authormanuscript;availableinPMC2023July27.Publishedinfinaleditedformas:Science.2023March4;331(6021):1199–1203.doi:10.1126/science.1202309.

NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-PAAuthorManuscript

DAXX/ATRX,MEN1andmTORPathwayGenesareFrequentlyAlteredinPancreaticNeuroendocrineTumorsYuchenJiao1,*,ChanjuanShi2,*,BarishH.Edil3,RoelandF.deWilde2,DavidS.Klimstra4,AnirbanMaitra5,RichardD.Schulick3,LauraH.Tang4,ChristopherL.Wolfgang3,MichaelA.Choti3,VictorE.Velculescu1,LuisA.DiazJr.1,6,BertVogelstein1,KennethW.Kinzler1,+,RalphH.Hruban5,+,andNickolasPapadopoulos1,+1LudwigCenterforCancerGeneticsandHowardHughesMedicalInstitutions,JohnsHopkinsKimmelCancerCenter,Baltimore,MD212312Department

ofPathology,theSolGoldmanPancreaticCancerResearchCenter,theJohnsHopkinsMedicalInstitutions,Baltimore,MD212313Department

ofSurgery,theSolGoldmanPancreaticCancerResearchCenter,theJohnsHopkinsMedicalInstitutions,Baltimore,MD212314Department

ofPathology,MemorialSloan-KetteringCancerCenter,NewYork,NY10065

5Departments

ofPathologyandOncology,theSolGoldmanPancreaticCancerResearchCenter,theJohnsHopkinsMedicalInstitutions,Baltimore,MD212316Swim

AcrossAmericaLaboratoryatJohnsHopkins,Baltimore,MD21231

AbstractPancreaticNeuroendocrineTumors(PanNETs)areararebutclinicallyimportantformofpancreaticneoplasia.ToexplorethegeneticbasisofPanNETs,wedeterminedtheexomicsequencesoftennon-familialPanNETsandthenscreenedthemostcommonlymutatedgenesin58additionalPanNETs.Remarkably,themostfrequentlymutatedgenesspecifyproteinsimplicatedinchromatinremodeling:44%ofthetumorshadsomaticinactivatingmutationsinMEN-1,whichencodesmenin,acomponentofahistonemethyltransferasecomplex;and43%hadmutationsingenesencodingeitherofthetwosubunitsofatranscription/chromatinremodelingcomplexconsistingofDAXX(death-domainassociatedprotein)andATRX(alphathalassemia/mentalretardationsyndromeX-linked).Clinically,mutationsintheMEN1andDAXX/ATRXgeneswereassociatedwithbetterprognosis.WealsofoundmutationsingenesinthemTOR(mammaliantargetofrapamycin)pathwayin14%ofthetumors,afindingthatcouldpotentiallybeusedtostratifypatientsfortreatmentwithmTORinhibitors.PanNETsarethesecondmostcommonmalignancyofthepancreas.Theten-yearsurvivalrateofpatientswithPanNETsisonly40%(1-3).Theyareusuallysporadic,buttheycanariseinmultipleendocrineneoplasiatype1andmorerarelyinothersyndromes,includingvonHippel-Lindau(VHL)syndromeandtuberoussclerosis(4).“Functional”PanNETssecretehormonesthatcausesystemiceffects,while“Nonfunctional”PanNETsdonotandthereforecannotalwaysbereadilydistinguishedfromotherneoplasm

softhepancreas.NonfunctionalPanNETsgrowsilentlyandpatientsoftenpresentwitheitheran

+

Towhomcorrespondenceshouldbeaddressed.npapado1@(N.P.);rhruban@(R.H.H.);andkinzlke@(K.W.K.).*ContributedequallytothisworkThetermsofthesearrangementsaremanagedbytheJohnsHopkinsUniversityinaccordancewithitsconflict-of-interestpolicies.

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asymptomaticabdominalmassorsymptomsofabdominalpainsecondarytocompressionbyalargetumor.Surgicalresectionisthetreatmentofchoice,butmanypatientspresentwithunresectabletumorsorextensivemetastaticdisease,andmedicaltherapiesarerelativelyineffectiveinthesecases.

ThereiscurrentlyinsufficientinformationaboutthistumortoeitherpredictprognosisofpatientsdiagnosedwithPanNETsortodevelopcompaniondiagnosticsandpersonalizedtreatmentstoimprovediseasemanagement.BiallelicinactivationoftheMEN1gene,usuallythroughamutationinoneallelecoupledwithlossoftheremainingwild-typeallele,occursin25-30%ofPanNETs(5,6).MEN1isatumorsuppressorgenewhich,whenmutatedinthegermline,predisposestomultipleendocrineneoplasiatype1syndrome.ChromosomalgainsandlossesandexpressionanalyseshaverevealedcandidatelociforgenesinvolvedinthedevelopmentofPanNETs,butthesehavenotbeensubstantiatedbygeneticorfunctionalanalyses(7-9).

Togaininsightsintothegeneticbasisofthistumortype,wedeterminedtheexomicsequenceof~18,000protein-codinggenesinaDiscoverysetoftenwell-characterizedsporadicPanNETs.Aclinicallyhomogeneoussetoftumorsofhighneoplasticcellularityisessentialforthesuccessfulidentificationofgenesandpathwaysinvolvedinanytumortype.Thus,weexcludedsmallcellandlargecellneuroendocrinecarcinomasandstudiedonlysamplesthatwerenotpartofafamilialsyndromeassociatedwithPanNETs(tableS1)(1).Wemicrodisectedtumorsamplestoachieveaneoplasticcellularityof80%.DNAfromtheenrichedneoplasticsamplesandfrommatchednon-neoplastictissuefromtenpatientswasusedtopreparefragmentlibrariessuitableformassivelyparallelsequencing.ThecodingsequenceswereenrichedbycapturewiththeSureSelectEnrichmentSystemandsequencedusinganIlluminaGAIIxplatform(10).Theaveragecoverageofeachbaseinthetargetedregionswas101-foldand94.8%ofthebaseswererepresentedbyatleast10reads(tableS2).

Weidentified157somaticmutationsin149genesamongthetentumorsusedinthe

Discoveryset.Themutationspertumorrangedfrom8to23,withameanof16(tableS3).Ofthesemutations,91%werevalidatedbySangersequencing.ThereweresomeobviousdifferencesbetweenthegeneticlandscapesofPanNETsandthoseofpancreaticductaladenocarcinomas(PDAC,ref.11).First,therewere60%fewergenesmutatedpertumorinPanNETsthaninPDACs.Second,thegenesmostcommonlyaffectedbymutationin

PDACs(KRAS,TGF-βpathway,CDKN2A,TP53)wererarelyalteredinPanNETsandviceversa(Table1).Third,thespectrumofmutationsinPDACandPanNETweredifferent,withCtoTtransitionsmorecommoninPDACsthaninPanNETs,andCtoGtransversionsmorecommoninPanNETsthaninPDACs(tableS4).ThissuggeststhatmutationsinPanNETsandPDACarisethroughdifferentmechanisms,perhapsduetoexposuretodifferentenvironmentalcarcinogensorthroughtheactionofdifferentDNArepairpathways.Wenextselectedgenesforfurtheranalysisthatwerewell-documentedcomponentsofapathwaythatwasgeneticallyalteredinmorethanonetumor,becausealterationsinthesegenesaremostlikelytobeclinicallyrelevant.FourgenesweremutatedinatleasttwotumorsintheDiscoveryset:MEN1infive,DAXXinthree,PTENintwo,andTSC2intwo.ATRXwasmutatedinonlyonesampleintheDiscoveryset,butitsproductformsa

heterodimerwithDAXXandthereforeispartofthesamepathway,soitwasalsoevaluatedintheValidationset.Similarly,PIK3CAwasincludedbecauseitsproductispartofthemTORpathwaythatincludesPTENandTSC2(12-14).ThesequencesofthesegeneswerethendeterminedbySangersequencinginaValidationsetconsistingof58additionalPanNETsandtheircorrespondingnormaltissues(Fig.1,AandB).Intotal,somatic

Science.Authormanuscript;availableinPMC2023July27.

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mutationsinMEN1,DAXX,ATRX,PTEN,TSC2,andPIK3CAwereidentifiedin44.1%,25%,17.6%,7.3%,8.8%,and1.4%PanNETs,respectively(Table2).

Ofthe30mutationsinMEN1,25wereinactivatingmutations(18insertionsordeletions(indels),5nonsenseand2splice-sitemutations),whilefiveweremissense.Atleast11werehomozygous;intheothers,thepresenceof“contaminating”DNAfromnormalcellsmadeitdifficulttoreliablydistinguishheterozygousfromhomozygouschanges.MEN1encodesmenin,anuclearproteinthatactsasascaffoldtoregulategenetranscriptionbycoordinatingchromatinremodeling.ItisanessentialcomponentoftheMLLSET1-likehistone

methyltransferase(HMT)complex(15-19).Overall,MEN1wasmutatedin30ofthe68PanNETsusedintheDiscoveryandValidationsetscombined.

DAXXandATRXweremutatedin17and12PanNETs,respectively.NotumorwithamutationinDAXXhadamutationinATRX,consistentwiththeirpresumptivefunctionwithinthesamepathway.Overall29of68PanNETs(42.6%)hadamutationinthis

pathway.Therewere11insertionsordeletions(indels)and4nonsensemutationsinDAXX,andsixindelsand3nonsensemutationsinATRX.ThethreeATRXmissensemutationswerewithintheconservedhelicasedomainwhiletheDAXXmissensemutationswerenon-conservedchanges.FiveDAXXandfourATRXmutationswerehomozygous,indicatinglossoftheotherallele.Thehighratioofinactivatingtomissensemutationsinbothgenes

establishesthemasPanNETtumorsuppressorgenes.LossofimmunolabellingforDAXXandATRXcorrelatedwithmutationoftherespectivegene(fig.S1,AandB,andtableS5).Fromthesedata,wehypothesizethatbothcopiesofDAXXaregenerallyinactivated,onebymutationandtheothereitherbylossofthenon-mutatedalleleorbyepigeneticsilencing.WealsohypothesizethatbothcopiesofATRXareinactivated,onebymutationandtheotherbychromosomeXinactivation.Recently,ithasbeenshownthatDAXXisanH3.3-specifichistonechaperone(20).ATRXencodesforaproteinthatattheamino-terminushasanADD(ATRX-DNMTT3-DNMT3L)domainandacarboxy-terminalhelicasedomain.Almostallmissensediseasecausingmutationsarewithinthesetwodomains(21).DAXXandATRXinteractandbotharerequiredforH3.3incorporationatthetelomeresandATRXisalsorequiredforsuppressionoftelomericrepeat-containingRNAexpression(22-24).ATRXwasrecentlyshowntotargetCpGislandsandG-richtandemrepeats(25),whichexistclosetotelomericregions.

WeidentifiedfivePTENmutations,twoindelsandthreemissense;sixTSC2mutations,oneindel,onenonsenseandfourmissense;andonePIK3CAmissensemutation.PreviouslypublishedexpressionanalyseshaveindicatedthattheexpressionofgenesinthemTORpathwayisalteredinmostPanNETs(26,27).Ourdatasuggestthat,atleastatthegeneticlevel,onlyasubsetofPanNETshavealterationsofthispathway.ThisfindingmayhavedirectclinicalapplicationthroughprioritizationofpatientsfortherapywithmTORpathwayinhibitors.Everolimus(Afinitor,RAD-001,40-O-(hydroxyethyl)-rapamycin)hasbeenshowntoincreaseprogressionfreesurvivalinasubsetofPanNETpatientswithadvanceddisease(28).IfthemutationalstatusofgenescodingforproteinsinthemTORpathwaypredictsclinicalresponsetomTORinhibitors,itshouldbepossibletoselectpatientswhowouldbenefitmostfromanmTORinhibitorthroughanalysisofthesegenesinpatients’tumors(29,30).

All68tumorsevaluatedinthisstudywerefrompatientsundergoingaggressiveintervention(tableS6)andincludedpatientsundergoingcurativeresectionaswellasthosewith

metastaticdisease.Interestingly,mutationsinMEN1,DAXX/ATRXorthecombinationofbothMEN1andDAXX/ATRXwereassociatedwithprolongedsurvivalrelativetothosepatientswhosetumorslackedthesemutations(Fig.1,CandDandtableS7).Thiswas

particularlyevidentinpatientswithmetastaticdiseaseandwithmutationsinbothMEN1and

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外顯子組測序胃泌瘤素

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DAXX/ATRX:100%ofpatientswithPanNETsthathadthesemutationssurvivedatleasttenyearswhileover60%ofthepatientswithoutthesemutationsdiedwithinfiveyearsof

diagnosis(Fig.1D).OnepossibleexplanationforthedifferenceinsurvivalisthatmutationsinMEN1andDAXX/ATRXidentifyabiologicallyspecificsubgroupofPanNETs.

Insummary,wholeexomesequencingofpancreaticneuroendocrinetumorshasledtotheidentificationofnoveltumorsuppressorgenesandilluminatedthegeneticdifferences

betweenthetwomajorneoplasmsofthepancreas.ThemutationsmayservetoaidprognosisandprovideawaytoprioritizepatientsfortherapywithmTORinhibitors.

NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-PAAuthorManuscript

SupplementaryMaterial

RefertoWebversiononPubMedCentralforsupplementarymaterial.

Acknowledgments

WethankM.Whalenforexperttechnicalassistance.SupportedbyaresearchgrantfromtheCaringforCarcinoidFoundation,theLustgartenFoundationforPancreaticCancerResearch,theSolGoldmanPancreaticCancer

ResearchCenter,TheJosephL.RabinowitzFundforPancreaticCancerResearch,TheVirginiaandD.K.LudwigFundforCancerResearch,theRaymondandBeverlySacklerResearchFoundation,theAACRStandUpToCancer-DreamTeamTranslationalCancerResearchGrant,andNationalInstitutesofHealthgrantsCA57345,CA121113,P50CA062924,P01CA134292,andR01CA113669.N.P.,B.V.,L.D.,V.E.V.,andK.W.K.are

membersoftheScientificAdvisoryBoardofInostics,acompanythatisdevelopingtechnologiesforthemoleculardiagnosisofcancer.N.P.,B.V.,L.D.,V.E.V.,andK.W.K.areco-foundersofInosticsandPersonalGenome

DiagnosticsandaremembersoftheirScientificAdvisoryBoards.TheauthorsareentitledtoashareoftheroyaltiesreceivedbytheUniversityonsalesofproductsrelatedtogenesdescribedinthismanuscript.N.P.,B.V.,K.W.K.,L.D.,andV.E.VownInosticsandPersonalGenomeDiagnosticsstock,whichissubjecttocertainrestrictionsunderUniversitypolicy.

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外顯子組測序胃泌瘤素

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Figure1.

Science.Authormanuscript;availableinPMC2023July27.

外顯子組測序胃泌瘤素

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Table1

ComparisonofcommonlymutatedgenesinPanNETsandPDAC

c

NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-PAAuthorManuscript

aGenesMEN1DAXX,ATRXGenesinmTORpathway

TP53KRASCDKN2A

TGFBR1,SMAD3,SMAD4ab

PanNET44%43%15%3%0%0%0%

PDAC0%0%

b

0.80%85%100%25%38%

Includespointmutationsandindels.

DatafromJonesetal.,Science321,1801(2023).

c

Basedon68PanNETsand114PDACs.

Science.Authormanuscript;availableinPMC2023July27.

外顯子組測序胃泌瘤素

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外顯子組測序胃泌瘤素

#Sample

g.chr6:33395889CA(hom)

g.chr11:64331709CA(hom)

g.chr11:64332046AG(hom)

g.chr11:64333812_64333828delCACGGCTGGAGACACCC

g.chr11:64334105_64334108delTCGT(hom)

g.chr11:64331233_64331234delAG(hom)

g.chr11:64334070CA(hom)

g.chr11:64328587GT

g.chr11:64333993_64333999delAGGGATG(hom)

g.chr11:64333955delG

g.chr11:64330370GC

g.chr11:64333876delG

g.chr11:64334002delG(hom)

g.chr11:64329234GA

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g.chr11:64333781delC

g.chr11:64330291delA

g.chr11:64334063_64334079delGGCTCCTCTCGGCCCAG

g.chr11:64332045CT

g.chr11:64330369delG

g.chr11:64334139GA

g.chr11:64332023_64332023insCTGT

g.chr11:64333906_64333909delAGAC

g.chr11:64333906_64333909delAGAC

g.chr11:64332032delC(hom)

g.chr11:64331269TC

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c.667_668delCG(hom)

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GeneTranscriptAccession

Nucleotide(genomic)*

Nucleotide(cDNA)

PanNET133PTDAXXCCDS4776.1

Jiaoetal.

PanNET3PTMEN1CCDS8083.1

PanNET5PTMEN1CCDS8083.1

PanNET6PTMEN1CCDS8083.1

PanNET10PTMEN1CCDS8083.1

PanNET23PTMEN1CCDS8083.1

PanNET29PTMEN1CCDS8083.1

PanNET31PTMEN1CCDS8083.1

PanNET39PTMEN1CCDS8083.1

PanNET44PTMEN1CCDS8083.1

PanNET45PTMEN1CCDS8083.1

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Science.Authormanuscript;availableinPMC2023July27.

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NIH-PAAuthorManuscript

$Aminoacid(protein)Mutationtype

fs

fs

fs

p.W188X

fs

p.Q7X

fs

fs

fs

fs

c.IVS799-2AG

c.IVS669+1GT

fs

p.A169V

Indel

Indel

Indel