HPV整合致癌的分子机制及其在宫颈癌筛查中的应用研究

宫颈癌是严重危害我国妇女生命健康的重大疾病之一。已证实高危型人乳头瘤病毒（high risk human papillomavirus, HR-HPV）是宫颈癌的致病因素。目前基于HPV-DNA检测的宫颈癌初筛方法因发现宫颈病变的特异性和阳性预测值较低，导致了过度筛查和公众恐慌。项目组前期确定了与宫颈癌发生发展密切相关的HPV高频整合位点，首次提出HPV通过微同源的机制整合至人基因组驱动宫颈癌的发生。本项目拟在前期笃实研究基础上，解析宫颈上皮内瘤变回退和进展至宫颈癌过程中HPV整合特征和基因组特征，阐明HPV整合导致宿主宫颈上皮细胞发生恶性转化的分子基础；另一方面，从染色体三维空间结构上探索HPV整合位点基因调控网络，完善HPV整合致癌理论；由此开展以人群为基础的大样本、多中心临床队列研究，研发和验证基于HPV整合的检测新技术在宫颈癌筛查中的效能，建立新一代宫颈癌精准筛查策略。

Cervical cancer is one of the serious diseases threatening the life and health of Chinese women. Persistent infection of high-risk human papillomavirus (HPV) has been demonstrated to be a risk factor of cervical intraepithelial neoplasm (CIN) and cervical cancer, but the exact mechanism of carcinogenesis is not clear. The current screening method for cervical cancer based on HPV-DNA detection has resulted in excessive screening and public panic because of the low predictive value of cervical lesions and the specificity and positive predictive value of cervical lesions. Our preliminary studies have demonstrated the specific HPV integration hot-spots in the human genome, described a new concept of HPV non-random integration and revealed the direct relationship between HPV integration at the hot-spot genes and the onset of cervical carcinoma. Based on the preliminary reliable studies, the HPV integration and genomic characteristics in the process of cervical intraepithelial neoplasia regression and progression to cervical cancer will be analyzed, and the molecular basis of HPV integration induced cervical epithelial cells malignant transformation will be clarified through establishing stable and site-specific of HPV knock-in and knock-out cellular models. On the other hand, combining with Hi-C, RNA-seq and CHIP-seq technology, the HPV integration site gene regulatory network from the three dimensional spatial structure of chromosomes will be explored to improve the theory of HPV integrated carcinogenesis. Finally, a crowd based and multi-center clinical cohort study will be conducted to develop and verify the effectiveness of the new technology based on HPV integration in cervical cancer screening, in which establishing a new strategy for precise screening of cervical cancer.