宫颈癌HPV整合和基因组不稳定性的研究

发布时间：2018-03-31 09:01

本文选题：人乳头瘤病毒　切入点：整合　出处：《华中科技大学》2014年博士论文

【摘要】：目的为了研究HPV整合和基因组不稳定性在宫颈癌发生发展的意义,我们探索建立HPV整合-FISH技术,从宫颈癌标本原位角度研究HPV整合的特点；利用TP63和MYC的拷贝数和蛋白表达作为标记物,并且利用基因集富集分析方法,探索HPV整合和宿主基因拷贝数变化等基因组不稳定对宫颈癌发病的影响。方法我们建立了一套新的可推广的FISH探针制作方法,用来检测HPV和基因组内的任意基因。探索了宫颈癌标本中不同基因组位点HPV整合的出现频率；研究CIN和宫颈癌病人病变组织的石蜡切片,用ROC曲线分析TP63、MYC的拷贝数和蛋白表达鉴别宫颈癌和CIN的诊断效率；分析宫颈癌中主要激活的信号通路和过表达的基因的特征。结果新的FISH探针制作方法可以有效地检测出宫颈癌中HPV整合。HPV信号在宫颈癌癌中有弥散和点状形式。在宫颈癌内部癌细胞分为不同亚群。在8q24位点HPV整合的频率最高。TP63和MYC的拷贝数、蛋白表达水平,以及HPV整合阳性率都随着CIN向宫颈癌的进展而增加。TP63拷贝数扩增表现出很高的诊断效能。经典通路富集显示ATM信号通路在宫颈癌中被激活,宫颈癌中染色体3q区域容易出现过表达的基因。结论 HPV在宫颈癌中存在高频整合位点。TP63和MYC的拷贝数扩增和蛋白过表达,以及HPV整合阳性率都和CIN到宫颈癌的病程发展具有相关性。ATM信号通路的激活和通路内的过表达基因,染色体3q区域的DNA扩增和基因过表达也是宫颈癌的重要特征。进一步研究上述标记物有助于深入理解宫颈癌发病机制,以更好地指导宫颈癌的防治。
[Abstract]:PurposeIn order to study the significance of HPV integration and genomic instability in the occurrence and development of cervical cancer, we explored the establishment of HPV integration-fish technology, and studied the characteristics of HPV integration from the point of view of cervical cancer in situ.Using the copy number and protein expression of TP63 and MYC as markers, and using the method of gene set enrichment analysis, the effects of genomic instability such as HPV integration and variation of host gene copy number on the pathogenesis of cervical cancer were explored.MethodWe have established a new and extensible FISH probe method for the detection of any gene in HPV and genome.The frequency of HPV integration at different genomic sites in cervical cancer specimens was explored, and the paraffin sections of CIN and cervical cancer tissues were studied. The ROC curve was used to analyze the copy number and protein expression of TP63 HPV in the differential diagnosis of cervical cancer and CIN.To analyze the characteristics of major activated signaling pathways and overexpression genes in cervical cancer.ResultThe new method of FISH probe fabrication can effectively detect the diffusive and punctate forms of HPV integration.HPVsignal in cervical carcinoma.In cervical cancer, cancer cells are subdivided into different subsets.The frequency of HPV integration at 8q24 site was the highest. TP63 and MYC copy number, protein expression level, and HPV integration positive rate were all increased with the progression of CIN to cervical cancer.The enrichment of classical pathway showed that the ATM signaling pathway was activated in cervical cancer, and the 3q region of chromosome was prone to overexpression in cervical cancer.ConclusionThe high frequency integration site. TP63 and MYC copy number amplification and protein overexpression were found in cervical cancer, and the positive rate of HPV integration was correlated with the activation of CIN signal pathway and overexpression gene in the pathway.DNA amplification and gene overexpression in chromosome 3 Q are also important features of cervical cancer.Further study of these markers is helpful to understand the pathogenesis of cervical cancer and guide the prevention and treatment of cervical cancer.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.33

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