肿瘤防治的新挑战NewchallengesincancerpreventionTianjinNorthNetworktheautho课件

Cancer—

MolecularNetworkDisease

Chengshujun,Gaoyanning,

Zhangkaitai,XiaoTin

CancerInstitute,ChineseAcademyofMedicalSciences,PekingUnionMedicalCollege

Cancer—

MolecularNetworkDis1FortuneMagazine,March22,2019FortuneMagazine,March22,202

PersonalizedTherapyprogressandchallengePersonalizedTherapy3Breastcancerpatientswiththesamestagecanhavemarkedlydifferenttreatmentresponses.Theclinicalbehaviour(suchaslymphnodestatusandhistologicalgrade)failtoclassifyaccuratelyoutcome.Chemotherapyorhormonaltherapyreducesdistantmetastasesbyone-third,however70-80%ofthesepatientswouldnotdevelopeddistantmetastaseswithouttheadjuvanttreatment,thesepatientsmaynotbenefitfromthetreatment,andmaypotentiallysufferfromthesideeffects.(Nature,2019,VOl.415,530)Breastcancerpatientswithth4Breastcancerpatientswiththesamestagecanhavemarkedlydifferenttreatmentresponses.Theclinicalbehaviour(suchaslymphnodestatusandhistologicalgrade)failtoclassifyaccuratelyoutcome.Chemotherapyorhormonaltherapyreducesdistantmetastasesbyone-third,however70-80%ofthesepatientswouldnotdevelopeddistantmetastaseswithouttheadjuvanttreatment,thesepatientsmaynotbenefitfromthetreatment,andmaypotentiallysufferfromthesideeffects.(Nature,2019,VOl.415,530)Breastcancerpatientswithth5FDANewsFORIMMEDIATERELEASE

P07-13

February6,2019MediaInquiries:

.TheMammaPrinttestusesthelatestinmoleculartechnologytopredictwhetherexistingcancerwillmetastasize(spreadtootherpartsofapatient'sbody).

70genesactivityconfersinformationaboutthelikelihoodoftumorrecurrence.FDANews6

Imatinib(Glivec)Chronicmyelogenousleukemia(CML)Bcr-abltyrosinekinaseinhibitor.CMLpatientshavehigh-expressionofBcr-ablfusionprotein.Gefitinib(Iressa)(epidermalgrowthfactorreceptoptyrosinekinaseinhibitor)

LungadenocarcinomapatientswithrelativelyhighfrequencyofEGFRgenemutationHerceptinBreastcancerHer2monoclonalantibodyTtumorregression11-26%forunselectedbreastcancerpatients,

34%forHER2-positivebreastcancerpatients(NatureReviewcancer,2019,6:735-741)

Imatinib(Glivec)Chronicmye7Wood,LD,et.al(Science,2019,Nov.16,Vol.318:1108)isolatedDNAfrom11breastand11colorectaltumorsanddeterminedthesequencesbasedonexonsrepresenting20,857transcriptfrom18,191gene.Anygenethatwasmutatedinthetumorbutnotinnormaltissuefromthesamepatientswasanalyzedin24additionaltumors.Pathwayratherthanindividualgenesappeartogovernthecourseoftumorigenesis.Disruptionofapathwaybymutationinanyoneofitsgeneticcomponentswouldpresumablyleadtosimilarchangesingrowth.The<15drivermutationinanindividualtumorlikelyreflectalterationsinasimilarnumberofpathways.Wood,LD,et.al(Science,2019,8Afewgene‘mountains’aremutatedinalargeproportionoftumors;mostgenesaremutatedin<5%oftumorsrepresentedas‘hills’两个肿瘤突变基因重复的很少，(Science2019,318:1108)Afewgene‘mountains’aremut9Greenman,Cetal(Nature,2019,446:153-)reported1,000somaticmutationsfoundinthecodingexonsof518proteinkinasegenesin210diversehumancancers.Therewassubstantialvariationinthenumberandpatternofmutationsinindividualcancer.Mostsomaticmutationsarelikelytobe‘passengers’thatdonotcontributetooncogenesis.However,therewasevidencefor‘driver’mutationcontributingtothedevelopmentofthecancerstudiedinapproximately120genes.Greenman,Cetal(Nature,2019,10Thomas,RKetal.(Naturegenetics,2019,39:347-)determined238knownoncogenmutationacross1,000humantumorsamplesof17cancer

types.

Of17oncogensanalyzed,theyfound14tobemutatedatleastonce,and298(30%)samplescarriedatleastonemutationThomas,RKetal.(Naturegeneti11Sianjones,etal,Scienceexpress,2019,Sep.4,1-10

检查了24例胰腺癌的20661蛋白编码基因

Pancreaticcancercontainanaverageof63geneticalterations,themajorityofwhicharepointmutations.Thesealterationsdefinedacoresetof12cellularsignalingpathways

Sianjones,etal,Scienceexp12

1).

Wood,LD,et.aldeterminedthe乳腺癌和结直肠癌DNAsequencesbasedonexonsof20,857transcriptfrom

18,191gene.(Science,2019,Nov.16,Vol.318:1108)

2).ThomasRK,etal分析17类肿瘤238个oncogenes的突变(Naturegenetics,2019:39;153-)3).Greenman,C;etal.分析210个不同人的肿瘤的518proteinkinasegeneexons的突变

(Nature,2019,446::153-)ThemutatedgenesintwocolorectaltumorsoverlaptoonlyasmallextentPathwayratherthanindividualgenesappeartogovernthecourseoftumorigenesis.Disruptionofapathwaybymutationinanyoneofitsgeneticcomponentswouldpresumablyleadtosimilarchangesingrowth.Thedifferencesarelikelytobethebasisforthewidevariationintumorbehaviorandresponsivenesstotherapytheacquisitionofnumeroussomaticmutations,eachwithasmallfitnessadvantage,mayalsodrivetumourigenesis

1).Wood,LD,et.aldetermined13Molecularlesionsthatoccurinearlystageofcancerorinprecursorlesionsaremorelikelytohaveadirectinfluenceoncanceroccurrenceandprogressionthanthosethataccumulateatthelaterstageofcancerdevelopment.Amongthelatter,manyalterationsmaybeconsideredas’passengers’.Molecularlesionsthatoccu14

Next-generationsequencingCancer—WholeGenomeSequencingNext-generationseque15

Recurringmutationsfoundbysequencinganacutemyeloidleukemiagenome.

NEnglJMed.2009Sep10;361(11):1058-66

38-year-oldmanofEuropeanancestryDNAsamplesfromthepatient’sbonemarrowsampleandanormalskin-biopsyspecimenobtainedTheAMLgenomethatwesequencedcontainsapproximately750pointmutations,Weidentified12acquired(somatic)mutationswithinthecodingsequencesofgenesand52somaticpointmutationsinconservedorregulatoryportionsinthetumorsample.Fourofthe64mutationsoccurredinatleast1additionalAMLsamplein188samplesthatweretested

Recurringmutationsfoundby16

Acomprehensivecatalogueofsomaticmutationsfromahumancancergenome

Publishedonline16December2009.Nature08658

wehavesequencedthegenomesofamalignantmelanomaandalymphoblastoidcelllinefromthesamepersonWeidentified33,345somaticbasesubstitutions.

Atotalof32,325weresingle-baseand510weredouble-basesubstitutions

Acomprehensivecatalogueof17

Asmall-celllungcancergenomewithcomplexsignaturesoftobaccoexposure

/naturePublishedonline16December2009.Usingmassivelyparallelsequencingtechnology,wesequencedasmall-celllungcancercellline,NCI-H209,NCI-BL209(anEpstein–Barr-virus-transformedlymphoblastoidlinehasbeengeneratedfromthepatient.)toexplorethemutationalburdenassociatedwithtobaccosmoking.Atotalof22,910somaticsubstitutionswereidentified,including134incodingexons.Onemutationforevery15cigarettessmoked.

Asmall-celllungcancergeno18

Cancer–MolecularnetworkdiseasecausedbycellularabnormalgrowthanddifferentiationrelatedtodevelopmentalgenomeCancer–Molecularnetworkdi19PNAS,2019,104:8685-PNAS,2019,104:8685-20GeneExpressionProfilesinDifferentPhasesofHumanLungEmbryonicDevelopmentandTumorigenesis

GeneExpressionProfilesinDi21DevelopmentlandscapeEmbudEarlyFLMidFLAdultL(41kprobes)DevelopmentlandscapeEmbudEarl22肿瘤防治的新挑战NewchallengesincancerpreventionTianjinNorthNetworktheautho课件23DNAReplicationDNAReplicationPre-InitiationDNAstrandelongationE2FmediatedregulationofDNAreplicationE2FtranscriptionaltargetsatG1/SFOXM1transcriptionfactornetworkFoxOfamilysignalingG1/STransitionG2/MCheckpointsG2/MDNAdamagecheckpointG2/MTransitionMPhaseM/G1TransitionMitoticMetaphase/AnaphaseTransitionMitoticPrometaphaseMitoticProphaseMitoticSpindleCheckpointMitoticTelophase/CytokinesisThedynamicgeneexpressingpatternsinhumandevelopmentalprocessDNAReplicationDNAReplication24ClinicalSignificanceTheexpressionlevelofthesegeneswascorrelatedwithsurvivalcancerpatients.TypeofcancersAdenocarcinomaofthelung（242samples)117,125

samplesBrainCancer（268

samples）BreastCancer（1077samples）249,159,179,286

samplesClinicalSignificanceTheexpre25P=0.0407Survivalanalysisof49ADCpatientsP=0.041Overallsurvivalanalysisof49lungADCpatientsP=0.0407Survivalanalysisof26SurvivalanalysisofstageIlungADCpatients:therelationshipbetweenthedevelopmentrelatedgenesandtheprognosisofstageIlungADCpatients.SurvivalanalysisofstageIl27Survivalanalysisof191GliomapatientsP=0.0299P=0.0009Survivalanalysisof80GliomapatientsSurvivalanalysisofgliomapatients:Therelationshipbetweenthedevelopmentrelatedgenesandtheoverallsurvivalofpatientswithglioma.Survivalanalysisof191P=028Theexpressionlevelofdevelopmentrelatedgeneswasassociatedwiththerelapse-freesurvivalofthebreastcancerpatients,whichwasconfirmedin7independentdatasets,involving1300samples.Theexpressionlevelofdevelo29Theexpressionlevelofdevelopmentrelatedgeneswasassociatedwiththeoverallsurvivalofthebreastcancerpatients,whichwasconfirmedin3independentdatasets.Theexpressionlevelofdevelo30Theexpressionlevelofdevelopmentrelatedgeneswasassociatedwithboththeoverallsurvivalandtherelapse-freesurvivalofthebreastcancerpatientswithoutlymphnotemetastasis(N0).Theexpressionlevelofdevelo31ForthepatientstreatedwithTamoxifen,theexpressionlevelofthedevelopmentrelatedgeneswasassociatedwiththeirprognoses.Forthepatientstreatedwith32TheexpressionlevelofthedevelopmentrelatedgeneswasalsoassociatedwiththeprognosesofthepatientsnottreatedwithTamoxifen.Theexpressionlevelofthede33TheexpressionlevelofdevelopmentrelatedgeneswasassociatedwiththeElstonHistologicGradeofbreastcancer.MostpatientswithGrade1

breastcancer(goodprognosis)hadalowerexpressionlevelofthedevelopmentrelatedgenes.AndmostpatientswithGrade3(badprognosis)hadahigherexpressionlevel.However,thepatientswithGrade2,whoseprognosiswasunpredictableaccordingtoElstonHistologicGrade,couldstillbedividedintotwogroupswithdifferentexpressionlevelofdevelopmentrelatedgenes.Theexpressionlevelofdevelo34AndtheprognosisofthetwogroupsofElstonGrade2patientswassignificantlydifferent.Andtheprognosisofthetwog35Cancerpreventionandtreatment(presentandfuture)