1、基因組不穩(wěn)定與腫瘤細(xì)胞有絲分裂時(shí)染色體分離錯(cuò)誤導(dǎo)致子細(xì)胞中整條染色體非整倍體突變，或者DNA損傷引起染色體結(jié)構(gòu)改變，造成的基因易位、缺失、反轉(zhuǎn)、斷裂等統(tǒng)稱(chēng)為基因組不穩(wěn)定（genomic instability ） ADDIN EN.CITE ADDIN EN.CITE.DATA HYPERLINK l _ENREF_1 o Carvalho, 2016 #20 1, HYPERLINK l _ENREF_2 o Wickramasinghe, 2016 #1 2。保持遺傳完整性是細(xì)胞活力的關(guān)鍵過(guò)程，并且通過(guò)廣泛的修復(fù)途徑來(lái)實(shí)現(xiàn)。當(dāng)這個(gè)系統(tǒng)有缺陷時(shí)，它會(huì)產(chǎn)生基因組的不穩(wěn)定性，并導(dǎo)致染色體畸變和突

2、變的積累，這些染色體畸變和突變可能導(dǎo)致各種臨床表型，包括易患癌癥 HYPERLINK l _ENREF_3 o Rancoule, 2017 #2 ADDIN EN.CITE ADDIN EN.CITE.DATA 3。在每個(gè)細(xì)胞分裂中傳輸完整和穩(wěn)定的遺傳密碼依賴(lài)于不同的DNA修復(fù)系統(tǒng)。 其中一些基因的種系突變導(dǎo)致癌癥易感性，而體細(xì)胞突變常見(jiàn)于各種癌癥類(lèi)型，從而產(chǎn)生基因組不穩(wěn)定性。 結(jié)果，癌細(xì)胞變得更容易受到額外的DNA損傷 HYPERLINK l _ENREF_4 o Eberst, 2017 #24 ADDIN EN.CITE Eberst2017244242417Eberst, L.Bra

3、hmi, M.Cassier, P. A.Centre Leon-Berard, departement de medecine, 28, rue Laennec, 69008 Lyon, France. Electronic address: lauriane.eberstlyon.unicancer.fr.Centre Leon-Berard, departement de medecine, 28, rue Laennec, 69008 Lyon, France.DNA repair as a therapeutic targetBull CancerBulletin du cancer

4、Bull CancerBulletin du cancerBull CancerBulletin du cancer2017/11/152017Nov 10Nouvelles perspectives dans le ciblage therapeutique de la reparation de l'ADN.0007-45512913268110.1016/j.bulcan.2017.09.005Nlmfre4。有絲分裂檢控點(diǎn)缺陷、中心體復(fù)制或者姐妹染色單體分裂錯(cuò)誤等是染色體非整倍體突變形成的主要原因。整條染色體的不穩(wěn)定性可能導(dǎo)致原癌基因的拷貝數(shù)增加、腫瘤抑制基因的缺失，使得細(xì)胞

5、更容易適應(yīng)周?chē)h(huán)境的改變，最終形成腫瘤細(xì)胞 HYPERLINK l _ENREF_5 o Danforth, 2016 #3 ADDIN EN.CITE ADDIN EN.CITE.DATA 5-9。轉(zhuǎn)錄是所有活細(xì)胞中必不可少的過(guò)程。然而，轉(zhuǎn)錄也會(huì)使基因組DNA受到許多內(nèi)源性物質(zhì)的傷害。盡管各種機(jī)制在轉(zhuǎn)錄過(guò)程中保護(hù)DNA的完整性，但在正常細(xì)胞和惡性細(xì)胞中發(fā)生轉(zhuǎn)錄相關(guān)的基因組不穩(wěn)定性，如果不修復(fù)，可能導(dǎo)致基因組改變。許多研究已經(jīng)暗示在癌癥基因組中發(fā)現(xiàn)轉(zhuǎn)錄的基因組改變。因此，與轉(zhuǎn)錄相關(guān)的基因組不穩(wěn)定性可被認(rèn)為是癌癥發(fā)展的主要驅(qū)動(dòng)因素 HYPERLINK l _ENREF_10 o Bouliann

6、e, 2017 #26 ADDIN EN.CITE Boulianne20172610262617Boulianne, B.Feldhahn, N.Department of Medicine, Centre for Haematology, Imperial College London, London, UK.Transcribing malignancy: transcription-associated genomic instability in cancerOncogeneOncogeneOncogeneOncogeneOncogeneOncogene2017/11/072017N

7、ov 060950-92322910639410.1038/onc.2017.402Nlmeng10。事實(shí)上所有腫瘤細(xì)胞都伴隨基因組不穩(wěn)定，比如2/3的人類(lèi)腫瘤在細(xì)胞分裂過(guò)程中獲得額外的或者丟失整條染色體 HYPERLINK l _ENREF_1 o Carvalho, 2016 #20 ADDIN EN.CITE ADDIN EN.CITE.DATA 1。 HYPERLINK l _ENREF_10 o Sherr, 2002 #23 像是CDK4、Ras下游原癌基因、B-Raf異常表達(dá)都會(huì)導(dǎo)致基因組不穩(wěn)定 ADDIN EN.CITE ADDIN EN.CITE.DATA HYPERLINK

8、 l _ENREF_11 o Kamata, 2010 #12 11, HYPERLINK l _ENREF_12 o Cui, 2010 #13 12。DNA損傷修復(fù)相關(guān)功能或者DNA損傷應(yīng)答機(jī)制缺陷會(huì)造成染色體結(jié)構(gòu)改變。如DNA損傷應(yīng)答信號(hào)通路中的激酶ATM和CHK2功能缺陷會(huì)導(dǎo)致DNA損傷修復(fù)的缺失 HYPERLINK l _ENREF_2 o Wickramasinghe, 2016 #1 ADDIN EN.CITE Wickramasinghe2016121117Wickramasinghe, V. O.Venkitaraman, A. R.Medical Research Coun

9、cil Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK. Electronic address: vw222mrc-cu.cam.ac.uk.Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK. Electronic address: arv22mrc-cu.cam.ac.uk.RNA Processing and Genome Stability: Caus

10、e and ConsequenceMol CellMolecular cellMol CellMolecular cellMol CellMolecular cell496-5056142016/02/20DNA DamageDNA Repair*Genome, Human*Genomic InstabilityHumansRNA/*metabolism*RNA Processing, Post-TranscriptionalSignal Transduction2016Feb 181097-27652689542310.1016/j.molcel.2016.02.001Nlmeng2。這些損

11、傷修復(fù)系統(tǒng)中涉及幾個(gè)基因，特定的多態(tài)性可預(yù)測(cè)癌癥的發(fā)生，最好的描述是BRCA HYPERLINK l _ENREF_3 o Rancoule, 2017 #2 ADDIN EN.CITE ADDIN EN.CITE.DATA 3。目前以基因組不穩(wěn)定為切入點(diǎn)治療腫瘤也取得了一定進(jìn)展。高水平的染色體非整倍體突變會(huì)導(dǎo)致細(xì)胞死亡，通過(guò)增加染色體非整倍體突變根除腫瘤細(xì)胞的已經(jīng)在體外得到驗(yàn)證；腫瘤細(xì)胞中心粒復(fù)制頻率較高，用灰黃霉素或有絲分裂相關(guān)蛋白HSET和HC1的干擾RNA可以有效抑制中心粒高復(fù)制的腫瘤細(xì)胞的增殖；針對(duì)腫瘤細(xì)胞染色體非整倍體的特性，有三種藥可以抑制三倍體的小鼠胚胎纖維細(xì)胞和非整倍體人細(xì)胞

12、的增殖；一些腫瘤中獲得或缺失的染色體是特定的，如腫瘤中常缺失7號(hào)染色體，50%的子宮腺癌缺失22號(hào)染色體，可以以此為切入點(diǎn)進(jìn)行治療；染色體結(jié)構(gòu)大量突變也會(huì)導(dǎo)致細(xì)胞死亡，5-FU和奧沙利鉑通過(guò)誘導(dǎo)DNA損傷有效的治療結(jié)腸癌 HYPERLINK l _ENREF_13 o Rebacz, 2007 #16 ADDIN EN.CITE ADDIN EN.CITE.DATA 13-18。此外，有研究發(fā)現(xiàn)，端粒DNA損傷信號(hào)能調(diào)節(jié)癌癥干細(xì)胞的進(jìn)化和轉(zhuǎn)移 HYPERLINK l _ENREF_19 o Lagunas, 2017 #25 ADDIN EN.CITE Lagunas2017251925251

13、7Lagunas, A. M.Wu, J.Crowe, D. L.University of Illinois Cancer Center, Chicago, IL, USA.Telomere DNA damage signaling regulates cancer stem cell evolution, epithelial mesenchymal transition, and metastasisOncotargetOncotargetOncotargetOncotargetOncotargetOncotarget80139-801558462017/11/092017Oct 061

14、949-255329113290Pmc565518510.18632/oncotarget.20960Nlmeng19。對(duì)于DNA修復(fù)途徑，有研究對(duì)涉及的蛋白質(zhì)以及它們與細(xì)胞周期檢查點(diǎn)的密切關(guān)系進(jìn)行了描述 HYPERLINK l _ENREF_4 o Eberst, 2017 #24 ADDIN EN.CITE Eberst2017244242417Eberst, L.Brahmi, M.Cassier, P. A.Centre Leon-Berard, departement de medecine, 28, rue Laennec, 69008 Lyon, France. Electron

15、ic address: lauriane.eberstlyon.unicancer.fr.Centre Leon-Berard, departement de medecine, 28, rue Laennec, 69008 Lyon, France.DNA repair as a therapeutic targetBull CancerBulletin du cancerBull CancerBulletin du cancerBull CancerBulletin du cancer2017/11/152017Nov 10Nouvelles perspectives dans le ci

16、blage therapeutique de la reparation de l'ADN.0007-45512913268110.1016/j.bulcan.2017.09.005Nlmfre4。在過(guò)去的十年中，對(duì)癌癥的分子和基因組特征的了解得到了提高，這導(dǎo)致了成功的靶向治療和精準(zhǔn)癌癥藥物領(lǐng)域的發(fā)展。作為這些進(jìn)展的結(jié)果，患有選擇性分子改變的腫瘤的患者適合于針對(duì)獨(dú)特的分子異常進(jìn)行有針對(duì)性的治療 HYPERLINK l _ENREF_20 o Jenkins, 2017 #27 ADDIN EN.CITE Jenkins20172720272717Jenkins, R. W.Thumm

17、alapalli, R.Carter, J.Canadas, I.Barbie, D. A.Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; email: .Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, US

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