腫瘤防治的新挑戰(zhàn)-腫瘤異質(zhì)性,分子分型 及個(gè)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(gè)體化冶療)

中國(guó)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(guó)惡性腫瘤發(fā)病及死亡情況的回顧與預(yù)測(cè)預(yù)計(jì)在2020年，全球新發(fā)病例將達(dá)1500萬(wàn)(我國(guó)占1/5)，死亡1000萬(wàn)(我國(guó)占1/4)，現(xiàn)患病例3000萬(wàn)。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(gè)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(gè)oncogenes的突變(Naturegenetics,2007:39;153-)3).Greenman,C;etal.分析210個(gè)不同人的腫瘤的518proteinkinasegeneexons的突變(Nature,2007,446::153-)

兩個(gè)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(gè)腫瘤包含有多少個(gè)基因的改變，以及相互的作用機(jī)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(gè)體反應(yīng)不同，這是腫瘤分子分型和個(gè)體化冶療的基礎(chǔ)

腫瘤異質(zhì)性,分子型,及個(gè)體化冶療Systemsbiology

基因突變譜(SNP)（ArrayCGH）基因組甲基化譜基因表達(dá)譜MicroRNAs譜(Oncomirs)蛋白標(biāo)志譜染色體異常細(xì)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(wú)復(fù)發(fā)存活時(shí)間明顯低于無(wú)甲基化(N.ENGL.J.MED.2008,358:1118-)N0N+42個(gè)基因可區(qū)分肺癌淋巴結(jié)轉(zhuǎn)移(50%)分子標(biāo)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(xiàng))

Iscancermetastasispredeterminedandpredictable?

利用此153個(gè)有顯著差異的基因，在國(guó)際上首次建立了一個(gè)肝癌轉(zhuǎn)移的預(yù)測(cè)模型。這一模型預(yù)測(cè)待檢標(biāo)本的準(zhǔn)確率達(dá)90%以上。(YeQH,etal.NatMed,2003,9;416-423)NSCLC有淋巴結(jié)轉(zhuǎn)移與無(wú)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(dòng)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(xì)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(zhǎng)的時(shí)間，“癌前病變”的一個(gè)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(guò)程 異型增生發(fā)生癌變的危險(xiǎn)度增加41倍多；

控制癌前病變

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

(Drivers)oncanceroccurrenceandprogressionthanthosethataccumulateatthelaterstageofcancerdevelopment.Amongthelatter,manyalterationsmaybeconsideredas’passengers’

早期癌變預(yù)警標(biāo)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(lái)腫瘤早診研究趨勢(shì)：分子影像學(xué)體液中腫瘤分子標(biāo)志譜肺癌細(xì)胞正常細(xì)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(biāo)本驗(yàn)證檢測(cè)到肺癌相關(guān)游離（分泌）蛋白已有1000多種。通過(guò)對(duì)肺癌患者血漿的檢測(cè)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(jiàn)在人血漿中被檢出的報(bào)道。

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

(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(duì)雙胞胎，其中10,803(9,512對(duì))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(guó)植物學(xué)會(huì)創(chuàng)建者和執(zhí)行主任馬克·布魯蒙薩爾說(shuō)：“一種復(fù)雜的草本制劑得以作為處方藥進(jìn)入美國(guó)市場(chǎng)，這是近半個(gè)世紀(jì)以來(lái)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(zhǔn)。這一批準(zhǔn)實(shí)際上為一個(gè)新藥行業(yè)的建立鋪平了道路。”

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(biāo)志能否淮確預(yù)測(cè)腫瘤予后？

晚期病人帶瘤生存治療？多靶點(diǎn)綜合治療(個(gè)體化冶療)實(shí)現(xiàn)個(gè)體化治療，避免過(guò)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(gè)體

癌前病變占位病變預(yù)防予警、發(fā)現(xiàn)早診、早冶