腫瘤防治的新挑戰(zhàn)-腫瘤異質(zhì)性,分子分型 及個體化冶療

腫瘤防治的新挑戰(zhàn)

(腫瘤異質(zhì)性,分子分型,及個體化冶療)

中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院腫瘤研究所腫瘤醫(yī)院

程書鈞我國惡性腫瘤發(fā)病及死亡情況的回顧與預(yù)測預(yù)計在2020年，全球新發(fā)病例將達1500萬(我國占1/5)，死亡1000萬(我國占1/4)，現(xiàn)患病例3000萬。腫瘤防治模式Wood,LD,et.al(Science,2007,Nov.16,Vol.318:1108)isolatedDNAfrom11breastand11colorectaltumorsanddeterminedthesequencesbasedonexonsrepresenting20,857transcriptfrom18,191gene.Anygenethatwasmutatedinthetumorbutnotinnormaltissuefromthesamepatientswasanalyzedin24additionaltumors.Pathwayratherthanindividualgenesappeartogovernthecourseoftumorigenesis.Disruptionofapathwaybymutationinanyoneofitsgeneticcomponentswouldpresumablyleadtosimilarchangesingrowth.The<15drivermutationinanindividualtumorlikelyreflectalterationsinasimilarnumberofpathways.Afewgene‘mountains’aremutatedinalargeproportionoftumors;mostgenesaremutatedin<5%oftumorsrepresentedas‘hills’兩個腫瘤突變基因重復(fù)的很少，(Science2007,318:1108)Greenman,Cetal(Nature,2007,446:153-)reported1,000somaticmutationsfoundinthecodingexonsof518proteinkinasegenesin210diversehumancancers.Therewassubstantialvariationinthenumberandpatternofmutationsinindividualcancer.Mostsomaticmutationsarelikelytobe‘passengers’thatdonotcontributetooncogenesis.However,therewasevidencefor‘driver’mutationcontributingtothedevelopmentofthecancerstudiedinapproximately120genes.Thomas,RKetal.(Naturegenetics,2007,39:347-)determined238knownoncogenmutationacross1,000humantumorsamplesof17cancer

types.

Of17oncogensanalyzed,theyfound14tobemutatedatleastonce,and298(30%)samplescarriedatleastonemutation

1).

Wood,LD,et.aldeterminedthe乳腺癌和結(jié)直腸癌DNAsequencesbasedonexonsof20,857transcriptfrom

18,191gene.(Science,2007,Nov.16,Vol.318:1108)

2).ThomasRK,etal分析17類腫瘤238個oncogenes的突變(Naturegenetics,2007:39;153-)3).Greenman,C;etal.分析210個不同人的腫瘤的518proteinkinasegeneexons的突變(Nature,2007,446::153-)

兩個腫瘤之間突變基因重復(fù)的很少Pathwayratherthanindividualgenesappeartogovernthecourseoftumorigenesis.Disruptionofapathwaybymutationinanyoneofitsgeneticcomponentswouldpresumablyleadtosimilarchangesingrowth.Thedifferencesarelikelytobethebasisforthewidevariationintumorbehaviorandresponsivenesstotherapy

Theepigeneticprogenitormodelofcancer

Stem/progenitorcells表觀遺傳學(xué)(epigenetic)改變;Gatekeepermutation;Geneticandepigeneticinstability

Feinberg,APetal.(NatureReviewGenetics,2006,7:21-33)

我們還不清楚一個腫瘤包含有多少個基因的改變，以及相互的作用機理？但研究已揭示與癌變有關(guān)的基因參與的復(fù)雜性，造戌了腫瘤病人的個體反應(yīng)不同，這是腫瘤分子分型和個體化冶療的基礎(chǔ)

腫瘤異質(zhì)性,分子型,及個體化冶療Systemsbiology

基因突變譜(SNP)（ArrayCGH）基因組甲基化譜基因表達譜MicroRNAs譜(Oncomirs)蛋白標志譜染色體異常細胞組織DiffuselargeB-cell(DLBCL)(themostcommonsubtypeofnon-Hodgkin’slymphoma)

GerminalcentreB-likeDLBCL,toexpressgenescharacteristicofgerminalcentreBcell,hadasignificantbettersurvival.(LMO2,BCL6,FN1,expressionrelatedtolongersurvival)

ActivatedB-likeDLBCL,toexpressgenesnormallyinducedduringinvitroactivationofperipheralbloodBcells.(CCND2,SCYA3,BCL2.expressionrelatedtoshortersurvival)

(N.Engl.J.Med.2004,300:1828-1837)Breastcancerpatientswiththesamestagecanhavemarkedlydifferenttreatmentresponses.Theclinicalbehaviour(suchaslymphnodestatusandhistologicalgrade)failtoclassifyaccuratelyoutcome.Chemotherapyorhormonaltherapyreducesdistantmetastasesbyone-third,however70-80%ofthesepatientswouldnotdevelopeddistantmetastaseswithouttheadjuvanttreatment,thesepatientsmaynotbenefitfromthetreatment,andmaypotentiallysufferfromthesideeffects.(Nature,2002,VOl.415,530)FDANewsFORIMMEDIATERELEASE

P07-13

February6,2007MediaInquiries:

.TheMammaPrinttestusesthelatestinmoleculartechnologytopredictwhetherexistingcancerwillmetastasize(spreadtootherpartsofapatient'sbody).

70genesactivityconfersinformationaboutthelikelihoodoftumorrecurrence.MicroRNA(miRNAs300-1000)areanabundantclassofnegativegeneregulatorsthathavebeenshowntocontrolawiderangeofbiologicalfunctionssuchascellularproliferation,differentiationandapoptosis.AbouthalfoftheannotatedhumanmiRNAsmapwithinfragileregionofchromosomes,whichareareasofthegenomethatareassociatedwithvarioushumancancers.miRNAmutationsormis-expressioncorrelatewithvarioushumancancersandcanfunctionastumorsuppressorsandoncogenes.

AsinglemiRNAmightbindasmanyas200gegetargetsandso,miRNAspotentiallycontroltheexpressionofaboutone-thirdofhumanmRNAs.

NatureReviews/Cancer2006,6;259-269Luetal.(Nature,2005435:834-)NENGLJMED2006,355:570-NENGLJMED2006,355:570-MethylationofthepromotorregionsofP16andCDH13inbothtumorandmediastinallymphnodesinstage1NSCLCpatientswasassociatedwithanoddsratioofrecurrentcancerof15.5.有甲基化病人無復(fù)發(fā)存活時間明顯低于無甲基化(N.ENGL.J.MED.2008,358:1118-)N0N+42個基因可區(qū)分肺癌淋巴結(jié)轉(zhuǎn)移(50%)分子標志譜在判斷乳腺癌治療敏感性中的應(yīng)用

(北京市科委重大專項)

Iscancermetastasispredeterminedandpredictable?

利用此153個有顯著差異的基因，在國際上首次建立了一個肝癌轉(zhuǎn)移的預(yù)測模型。這一模型預(yù)測待檢標本的準確率達90%以上。(YeQH,etal.NatMed,2003,9;416-423)NSCLC有淋巴結(jié)轉(zhuǎn)移與無淋巴結(jié)轉(zhuǎn)移病人比較,前者有1q25-32,12q23-24.3,17q12-22區(qū)域DNA拷貝增加，而且這種差別在原位癌階段即已形成,提示在原位癌階段即可能巳經(jīng)有與轉(zhuǎn)移相關(guān)的drivergenes在不斷推動以后的肺癌轉(zhuǎn)移(J,Ma.etal.

JPathl2006,210:205-213),癌前病變與癌癌變的多階段發(fā)生模式從正常細胞發(fā)展到危及生命的惡性腫瘤，大多經(jīng)歷“癌前病變”階段。而從“癌前病變”發(fā)展成侵襲性癌一般需要10年或更長的時間，“癌前病變”的一個重要特征是具有可逆性。正常增生輕度不典型增生原位癌侵襲癌轉(zhuǎn)移癌10－30年癌前病變正?；驕\表性胃炎慢性萎縮性胃炎腸上皮型化生異型增生胃癌胃粘膜多階段癌變過程 異型增生發(fā)生癌變的危險度增加41倍多；

控制癌前病變

Tamoxifen為什么有些癌前病變會發(fā)展成為浸襲性癌？而大部分不會？Molecularlesionsthatoccurinearlystageofcancerorinprecursorlesionsaremorelikelytohaveadirectinfluence

(Drivers)oncanceroccurrenceandprogressionthanthosethataccumulateatthelaterstageofcancerdevelopment.Amongthelatter,manyalterationsmaybeconsideredas’passengers’

早期癌變預(yù)警標志

腫瘤早期發(fā)現(xiàn)和診斷是腫瘤治療的關(guān)鍵肺癌Stage1病人5年生存率70%左右

StageIV病人5年生存率5%左右未來腫瘤早診研究趨勢：分子影像學(xué)體液中腫瘤分子標志譜肺癌細胞正常細胞空培養(yǎng)基原代培養(yǎng)收集條件培養(yǎng)基濃縮、凍干1-DSDS電泳質(zhì)譜鑒定臨床組織標本驗證檢測到肺癌相關(guān)游離（分泌）蛋白已有1000多種。通過對肺癌患者血漿的檢測分析，已鑒定出11種蛋白，8種明顯差異（增高或降低，如MMP1、Fascin、CD98、SC、14-3-3-eta、-sigma、-beta、LAMC2)，其中有7種未見在人血漿中被檢出的報道。

這也是目前國際上同類研究中最大的一個腫瘤相關(guān)分泌／釋放蛋白數(shù)據(jù)庫

(Molecular&CellularProteomics2005,4:1480)人類控制腫瘤的關(guān)鍵

內(nèi)在遺傳因素:

在北歐瑞典、丹麥、芬蘭研究了44,788對雙胞胎，其中10,803(9,512對)人發(fā)生腫瘤，表明有遺傳因素影響的腫瘤是：前列腺癌42%大腸、直腸癌35%乳腺癌27%(N.Eng.J.Med.2000,342:78-85)

Firstpatient-appliedtherapyfortreatmentofexternalgenitalandperianalwarts

in10years

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AmericanBotanicalCouncil(Austin,Texas,Nov9,2006)”非贏利的美國植物學(xué)會創(chuàng)建者和執(zhí)行主任馬克·布魯蒙薩爾說：“一種復(fù)雜的草本制劑得以作為處方藥進入美國市場，這是近半個世紀以來的第一次。”

“這種新藥,其安全和功效已經(jīng)得到了充分的臨床證明，并且跟所有化學(xué)或生物藥物一樣獲得了FDA的批準。這一批準實際上為一個新藥行業(yè)的建立鋪平了道路?！?/p>

Whatwedon’tknow

一種基因能治好晚期腫瘤？一種藥物能否治好晚期腫瘤？單一生物標志能否淮確預(yù)測腫瘤予后？

晚期病人帶瘤生存治療？多靶點綜合治療(個體化冶療)實現(xiàn)個體化治療，避免過度治療，是改善目前腫瘤治愈率低和死亡率高的有效途徑。

高危個體

癌前病變占位病變預(yù)防予警、發(fā)現(xiàn)早診、早冶