基因组不稳定与肿瘤

1、基因组不稳定与肿瘤细胞有丝分裂时染色体分离错误导致子细胞中整条染色体非整倍体突变，或者DNA损伤引起染色体结构改变，造成的基因易位、缺失、反转、断裂等统称为基因组不稳定（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。保持遗传完整性是细胞活力的关键过程，并且通过广泛的修复途径来实现。当这个系统有缺陷时，它会产生基因组的不稳定性，并导致染色体畸变和突

2、变的积累，这些染色体畸变和突变可能导致各种临床表型，包括易患癌症 HYPERLINK l _ENREF_3 o Rancoule, 2017 #2 ADDIN EN.CITE ADDIN EN.CITE.DATA 3。在每个细胞分裂中传输完整和稳定的遗传密码依赖于不同的DNA修复系统。 其中一些基因的种系突变导致癌症易感性，而体细胞突变常见于各种癌症类型，从而产生基因组不稳定性。 结果，癌细胞变得更容易受到额外的DNA损伤 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。有丝分裂检控点缺陷、中心体复制或者姐妹染色单体分裂错误等是染色体非整倍体突变形成的主要原因。整条染色体的不稳定性可能导致原癌基因的拷贝数增加、肿瘤抑制基因的缺失，使得细胞

5、更容易适应周围环境的改变，最终形成肿瘤细胞 HYPERLINK l _ENREF_5 o Danforth, 2016 #3 ADDIN EN.CITE ADDIN EN.CITE.DATA 5-9。转录是所有活细胞中必不可少的过程。然而，转录也会使基因组DNA受到许多内源性物质的伤害。尽管各种机制在转录过程中保护DNA的完整性，但在正常细胞和恶性细胞中发生转录相关的基因组不稳定性，如果不修复，可能导致基因组改变。许多研究已经暗示在癌症基因组中发现转录的基因组改变。因此，与转录相关的基因组不稳定性可被认为是癌症发展的主要驱动因素 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。事实上所有肿瘤细胞都伴随基因组不稳定，比如2/3的人类肿瘤在细胞分裂过程中获得额外的或者丢失整条染色体 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异常表达都会导致基因组不稳定 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损伤修复相关功能或者DNA损伤应答机制缺陷会造成染色体结构改变。如DNA损伤应答信号通路中的激酶ATM和CHK2功能缺陷会导致DNA损伤修复的缺失 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。这些损

11、伤修复系统中涉及几个基因，特定的多态性可预测癌症的发生，最好的描述是BRCA HYPERLINK l _ENREF_3 o Rancoule, 2017 #2 ADDIN EN.CITE ADDIN EN.CITE.DATA 3。目前以基因组不稳定为切入点治疗肿瘤也取得了一定进展。高水平的染色体非整倍体突变会导致细胞死亡，通过增加染色体非整倍体突变根除肿瘤细胞的已经在体外得到验证；肿瘤细胞中心粒复制频率较高，用灰黄霉素或有丝分裂相关蛋白HSET和HC1的干扰RNA可以有效抑制中心粒高复制的肿瘤细胞的增殖；针对肿瘤细胞染色体非整倍体的特性，有三种药可以抑制三倍体的小鼠胚胎纤维细胞和非整倍体人细胞

12、的增殖；一些肿瘤中获得或缺失的染色体是特定的，如肿瘤中常缺失7号染色体，50%的子宫腺癌缺失22号染色体，可以以此为切入点进行治疗；染色体结构大量突变也会导致细胞死亡，5-FU和奥沙利铂通过诱导DNA损伤有效的治疗结肠癌 HYPERLINK l _ENREF_13 o Rebacz, 2007 #16 ADDIN EN.CITE ADDIN EN.CITE.DATA 13-18。此外，有研究发现，端粒DNA损伤信号能调节癌症干细胞的进化和转移 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。对于DNA修复途径，有研究对涉及的蛋白质以及它们与细胞周期检查点的密切关系进行了描述 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。在过去的十年中，对癌症的分子和基因组特征的了解得到了提高，这导致了成功的靶向治疗和精准癌症药物领域的发展。作为这些进展的结果，患有选择性分子改变的肿瘤的患者适合于针对独特的分子异常进行有针对性的治疗 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

18、A.Molecular and Genomic Determinants of Response to Immune Checkpoint Inhibition in CancerAnnu Rev MedAnnual review of medicineAnnu Rev MedAnnual review of medicineAnnu Rev MedAnnual review of medicine2017/11/042017Nov 030066-42192909967610.1146/annurev-med-060116-022926Nlmeng20。或许在不久的将来，我们能够根据基因组不稳

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