前列腺癌的DNA修復(fù)缺陷及分子分型

前列腺癌的DNA修復(fù)缺陷及分子分型

2017.3.10

OlaparibDNA-RepairDefectsinProstateCancerMolecularsubtypingofprostatecancerGenomichallmarksofprostatecancer前列腺癌是男性常見(jiàn)腫瘤之一，在全球范圍內(nèi)，前列腺癌發(fā)病率在男性所有惡性腫瘤中居第二位。雖然大多數(shù)前列腺癌患者是局部、可治愈的，但是每年全世界仍有超過(guò)20萬(wàn)男性由于前列腺癌轉(zhuǎn)移而死亡。在美國(guó)前列腺癌的發(fā)病率已經(jīng)超過(guò)肺癌，成為第一位危害男性健康的腫瘤。2016年美國(guó)新增病例180890例，死亡病例約26120例。GenomicaberrationsintheDNAdamagerepairpathwayarecommoninPC,particularlyinlate-stagedisease,andmayberelevantfortreatmentstratification.DNArepairdefectsplayarelevantroleincarcinogenesisandPCprogression

Prostatecarcinogenesisismediated,asinothercancers,bytheaccumulationofgeneticandepigeneticaberrations;thesemolecularchangescanbeinheritedorbetheresultofalteredARtranscriptionalactivity,changesinchromatinarchitecture,oncogenicreplication,error-proneDNArepair,ordefectivecelldivision.

InheritedmutationsinDNArepairgenesandPCrisk

HereditarygermlinemutationsinDNArepairgenesareassociatedwithahigherriskofPCGermlinemutationsinBRCA2increasetheriskofdevelopingPC(relativerisk8.6inmen<65yr),Moreover,inheritedmutationsinotherDNArepairgenessuchasPALB2,MLH1,MSH2,andPMS2alsoappeartobeassociatedwithPCrisk.

ageatdiagnosisandfamilyhistoryofPCdidnotidentifythemutationcarriers,althoughtherewasenrichmentamongpatientswithafamilyhistoryofcancer.

ImpactofDNArepairdefectsonclinicaloutcomeinPCTherelevanceofsomaticlossoffunctionofDNArepairgenesinthetreatmentofCRPCisstillnotclear.Inaseriesofmorethan2000patientswithlocalizedPC,including61BRCA2and18BRCA1mutationcarriers,23%ofgBRCA1/2mutationcarriersdevelopedmetastasisafter5yrofradicaltreatment,comparedto7%ofnoncarriers(p=0.001).Cause-specificsurvivalwassignificantlyshorteramongcarriers(8.6

yr)comparedtononcarriers(15.7yr).SubgroupanalysisconfirmedgBRCA2mutationsasindependentfactorforpoorprognosis.DNADAMAGEREPAIRMECHANISMSDNADAMAGEREPAIRMECHANISMSOLAPARIB(A)DNArepairundernormalconditions.Singlestrandbreaks(SSBs)anddoublestrandbreaks(DSBs)arepreferentiallyrepairedbyerror-freemechanismsthatincludepoly(ADP‐ribose)polymerase(PARP)and(BRCA)1/2,respectively.(B)SyntheticlethalityofolaparibinBvRCA‐associatedcancercells.Withbotherror‐freerepairmechanismsblocked,DNAcanonlyberepairedwithmoreerror‐pronerepairmechanisms.Theresultingbuild‐upofDSBsanderroneousDNAultimatelyleadstocelldeathOLAPARIBPARP抑制劑的開(kāi)發(fā)經(jīng)歷許多曲折，Olaparib是近半個(gè)世紀(jì)研究的產(chǎn)物。研究表明PARPs可幫助修復(fù)DNA損傷。如果得不到修復(fù)，DNA雙鏈斷裂會(huì)觸發(fā)細(xì)胞死亡。抑制該酶的作用不太可能殺死健康細(xì)胞，因?yàn)榻】导?xì)胞擁有多條修復(fù)斷裂DNA的信號(hào)通路。但癌細(xì)胞有時(shí)候會(huì)發(fā)生一些突變，破壞其他類(lèi)型的修復(fù)，使得它們尤其對(duì)PARP抑制敏感。因此，以這種機(jī)制發(fā)揮作用的藥物可在靶向癌細(xì)胞的同時(shí)，繞過(guò)健康細(xì)胞，避免了一些毒副作用。OLAPARIBCLINIALTRIAL-TOPARPTOPARP-A的臨床II期試驗(yàn)50名轉(zhuǎn)移性CRPC接受了olaparib（400

mg，BID）治療，之前患者都接受過(guò)多西他賽治療，有49人接受過(guò)阿比特龍或恩雜魯胺治療，而且有29人接受過(guò)卡巴他賽治療。主要研究終點(diǎn)：ORR。療效標(biāo)準(zhǔn)為：客觀標(biāo)準(zhǔn)(RECIST1.1)或PSA水平降低50%或血液中CTC從≥5個(gè)/7.5ml血液降低到少于5個(gè)/7.5ml。16人（33%）對(duì)olaparib治療有反應(yīng)。Olaparib治療阻止了前列腺癌生長(zhǎng)，導(dǎo)致PSA水平持久下降，血液中循環(huán)腫瘤細(xì)胞計(jì)數(shù)下降。患者對(duì)該藥物的持續(xù)反應(yīng)時(shí)間為大于6個(gè)月。最常見(jiàn)的AE貧血（10人，20%）和疲勞（6人，6%)。TOPARP-A的臨床II期試驗(yàn)通過(guò)NGS，試驗(yàn)發(fā)現(xiàn)30%的mPC患者腫瘤DNA修復(fù)系統(tǒng)存在缺陷（如BRCA1/2、ATM、CHEK2等基因缺失或突變）——這些患者尤其對(duì)olaparib反應(yīng)良好。16名攜帶可檢測(cè)DNA修復(fù)突變患者中，14人（14/16，88%）對(duì)olaparib反應(yīng)良好。大多數(shù)是mPC，其疾病控制時(shí)間比這組患者預(yù)期的時(shí)間要長(zhǎng)得多。全部7名BRCA2缺失（4名體細(xì)胞缺失，3名胚系細(xì)胞突變）、5位ATM基因異?；颊?位對(duì)治療有反應(yīng)。這些結(jié)果促成啟動(dòng)臨床試驗(yàn)TOPARP-B，讓攜帶可檢測(cè)DNA修復(fù)突變的前列腺癌患者接受olaparib治療。約翰霍普金斯大學(xué)的DungT.Le教授在2015年的ACSO會(huì)議上報(bào)道了PD-1抑制劑Keytruda的一個(gè)2期臨床實(shí)驗(yàn)結(jié)果（NCT01876511）。有意思的是和PARP抑制劑類(lèi)似，40個(gè)受試者中，其中10個(gè)包括胃癌、小腸癌、和卵巢癌有DNA錯(cuò)配修復(fù)缺陷患者的應(yīng)答率高達(dá)71%。相反錯(cuò)配修復(fù)功能完好的患者對(duì)Keytruda沒(méi)有表現(xiàn)應(yīng)答。PARP抑制劑和抗PD-1抗體都對(duì)DNA缺陷患者敏感，能否將兩者聯(lián)合使用或能顯示協(xié)同效應(yīng)，成為治療這類(lèi)患者的利器（比如DNA修復(fù)突變患者在前列腺癌中占30%左右）。利用基因組測(cè)序來(lái)檢測(cè)攜帶特定可靶向突變的腫瘤治療（也就是精準(zhǔn)醫(yī)學(xué)）是將來(lái)發(fā)展的方向。DNA-RepairGeneMutionsDNA-RepairGeneMutions分析了６９２例無(wú)法因家族易感性或診斷年齡選擇的轉(zhuǎn)移性前列腺癌患者，應(yīng)用全外顯子序列或靶基因下游序列的多元分析方法，評(píng)估癌癥易感相關(guān)的２０個(gè)ＤＮＡ修復(fù)基因的突變情況。研究結(jié)果顯示８４種ＤＮＡ突變?cè)冢福怖砩系玫津?yàn)證（１１.８％）。在８４例的基因突變中，截短突變?yōu)椋罚估?，錯(cuò)義突變?yōu)椋道?。而突變的１６個(gè)基因中，ＢＲＣＡ２所占的比例最高（４４％），其次為ＡＴＭ（１３％）、ＣＨＥＫ２（１２％）、ＢＲＣＡ１（７％）、ＲＡＤＳ１Ｄ（４％）、ＰＡＬＢ２（４％）?；蛲蛔冾l率與是否具有前列腺癌家族史、患者的診斷年齡以及種族則無(wú)相關(guān)性。對(duì)４９９例局灶性前列腺癌患者的分析顯示，其ＤＮＡ修復(fù)基因突變的頻率明顯降低（４．６％）。綜上所述，在研究人員的多中心研究中，轉(zhuǎn)移性前列腺癌患者中ＤＮＡ修復(fù)基因突變頻率為１１．８％，較局灶性前列腺癌患者明顯增高，并且與前列腺癌家族史及患者的診斷年齡無(wú)關(guān)。DNA-RepairGeneMutionsDNA-RepairGeneMutionsDNA-RepairGeneMutionsMolecularTaxonomyofPC基于Gleason評(píng)分、PSA水平、臨床、病理分期所組成的風(fēng)險(xiǎn)級(jí)。InthecurrenteraofPSAscreening,nearly90%ofprostatecancersareclinicallylocalizedatthetimeoftheirdiagnosis.Theclinicalbehavioroflocalizedprostatecancerishighlyvariable–whilesomemenwillhaveaggressivecancerleadingtometastasisanddeathfromthedisease,manyotherswillhaveindolentcancersthatarecuredwithinitialtherapyormaybesafelyobserved.Furtherriskstratificationusingmolecularfeaturescouldpotentiallyhelpdistinguishindolentfromaggressiveprostatecancer.MolecularTaxonomyofPCTogainfurtherinsightintothemolecular-geneticheterogeneityofprimaryprostatecancerandtoestablishamoleculartaxonomyofthediseaseforfuturediagnostic,prognostic,andtherapeuticstratification,theTCGANetworkhascomprehensivelycharacterized333primaryprostatecancersusingsevengenomicplatforms.Thisanalysisrevealsnovelmolecularfeaturesthatprovideabetterunderstandingofthisdiseaseandsuggestpotentialtherapeuticstrategies.MolecularTaxonomyofPCWecharacterizedisolatedbiomoleculesfromthese333tumorsamplesusingfourplatforms:1.whole-exomesequencingforsomaticmutations,2.3.array-basedmethodsforprofilingbothsomaticcopy-numberchangesandDNAmethylation,4.messengerRNA(mRNA)sequencing.5.microRNA(miRNA)sequencing

on330ofthesesamples,6.reverse-phaseproteinarray(RPPA)on152samples,7.low-passandhigh-passwhole-genomesequencing(WGS)on100and19tumor/normalpairs.MolecularTaxonomyofPCSevenMolecularsubtypesdefinedERG46%ETV18%ETV44%FLI11%SPOP11%FOXA13%IDH11%However,evenwithinthegroupstherewassignificantdiversityinDNAcopy-numberalterations,geneexpression,andDNAmethylation.Epigeneticprofilesshowedsubstantialheterogeneity,includinganIDH1-mutantsubsetwithamethylatorphenotype.Androgen

receptor(AR)activityvariedwidelyandinasubtype-specificmannerwithSPOPandFOXA1mutanttumorshavingthehighestlevelsofAR-inducedtranscripts.25%oftheprostatecancershadapresumedactionablelesioninthePI3KorMAPKsignalingpathways.DNA

repairgeneswereinactivatedin19%.MolecularTaxonomyofPCMolecularTaxonomyofPC前列腺癌的分子分型的探討仍在路上……Itprovidesaresourc