非可控性宫颈高危型HPV持续感染恶性转化的动态调控网络及其分子机制

宫颈癌是全球女性死因的第三大恶性肿瘤。非可控性宫颈高危型人乳头瘤病毒(Human Papillomavirus, HPV)持续性感染与宫颈癌前病变和癌变的发生关系密切。我们前期结果表明，遗传变异在宫颈癌易感性中起至关重要的作用，由微同源HPV非随机整合也与宫颈重大疾病发生相关。然而，在宫颈恶性转化演变过程中宿主遗传易感性与高危型HPV持续性感染如何相互作用从而启动了致癌靶点？如何评价和预测高危型HPV持续性感染的转归？本项目以同济医院妇科肿瘤数据库标本库和宫颈疾病专科为依托，利用独特资源选择极端病例，从宿主本身遗传变异调控网络、高危型HPV非可控整合模式、关键致癌靶点的特征性改变及肿瘤免疫逃逸机制等多方面阐明宫颈HPV持续性感染恶性转化的分子机制，为建立中国宫颈癌高危人群分子预警系统、圈定高危人群进行分层管理奠定理论基础，有利于预防关口前移，对保护妇女健康、节约国家疾病防治费用具重大意义。

Cervical cancer is the third leading cause of cancer-related mortality among women worldwide. The uncontrollable high-risk Human papilloma virus (HPV) persistent infection was closely related to cervical cancer. Our previous results indicated that the core immunological genetically variation plays a crucial role in the susceptibility to cervical cancer. Moreover, HPV nonrandom integration mechanism mediated by microhomology sequence is associated with cervical cancer. However, how do the host genetic susceptibility and high-risk HPV nonrandom integration interact with each other to launch the carcinogenic targets in the malignant transformation? How to evaluate and predict the outcome of high-risk HPV persistent infection? Based on Chinese gynecological oncology database and bio-bank and the cervical disease department in Tongji hospital, this project selects the extreme cases in unique resources. The molecular mechanisms of cervical malignant transformation induced by the uncontrollable HPV persistent infection will be clarifies in several aspects, such as, the host regulation network of genetic variations, HPV nonrandom integration and the key cancer targets in the process of the tumor immune escape, and so on. This study provides the solid theory foundation for clearing the pathogenesis of cervical cancer, establishing the molecular warning system for identifying Chinese high-risk groups for layered management. The benefit of earlier prevent measures is of great significance to protect the health of women and to decrease national cost of disease control and prevention.