Toll样受体基因遗传变异与宫颈癌易感性及其分子机制

Cervical cancer is one the most common cancer among women worldwide. Epidemiological and laboratory-based studies have identified the infection with one of 15 high-risk, or oncogenic, HPV types as a necessary but not sufficient cause of cervical cancer. The prevalence of genital HPV infections in developing countries is very high in young women, but most of the infections regress without intervention. Given the mounting evidence that long-term HPV infection is a prerequisite for cervical carcinogenesis, host genetic variations that influence the immune response of HPV clearance may determine the outcome of high risk HPV infection. Thus, it is crucial to investigate genetic risk factors which closely related with immune response to HPV clearance in cervical cancer development in general population. Toll-like receptors family (TLRs), a type of cell-surface signaling molecule, contribute to the host's innate immune system by recognizing pathogen-associated molecular patterns expressed in infectious agents, play a key role in host defense and clearance during HPV infection by regulating and linking the innate and Th1 immune responses. The aim of this case-control study is to investigate the associations of the polymorphisms of TLRs and interactions of gene-gene/environment with cervical cancer risk. This study may give an insight in biological mechanism of TLRs in development of cervical cancer and provide biomarkers for the disease risk predication.

宫颈癌是女性最常见的恶性肿瘤之一。高危人乳头瘤病毒（HPV）是公认的宫颈癌的致病因子，但仅少数高危HPV持续感染者最终发展为宫颈癌，提示遗传差异可能决定女性感染HPV后的不同结局。Toll样受体家族（Toll-like receptors family, TLRs）参与病原体的识别,与HPV的免疫清除相关。TLRs的功能改变或基因遗传多态性可能影响个体宫颈癌易感性。目前,国内外有关TLRs基因遗传变异与宫颈癌易感性的研究较少，且存在样本量小等不足。本研究通过大样本的病例-对照研究，选择与HPV感染相关的TLRs基因，在数据库中筛选潜在功能性的SNPs，进行组间比较；检验其表达水平和体外分子生物学研究，阐明这些SNPs的生物学含义和基因型-表型关系，结合环境因素，分析基因-环境/基因-基因交互作用与宫颈癌发生的关系，旨在进一步阐明TLRs在HPV致宫颈癌发生中的分子遗传学机制，筛选高危人群。

宫颈癌是威胁全球妇女健康的主要恶性肿瘤之一，83%的宫颈癌发生在发展中国家，宫颈癌的发病呈现不断年轻化的趋势。目前已经公认高危HPV感染是宫颈癌发生的必要条件，但是高危HPV在生育年龄人群中的感染率达到15-20%，仅极少数高危HPV感染者会最终发展为宫颈癌。绝大部分高危HPV感染者不需干预2年内会自行消退，个体间在免疫系统上的遗传差异可能会影响机体对高危HPV的易感性及清除能力，进而决定了不同个体感染高危HPV后的结局。免疫系统对病原微生物的清除，始于其对病原微生物“非己”抗原的识别，Toll样受体家族（TLRs）是机体通过感知微生物病原体并激活细胞直接产生免疫防御的固有免疫受体，诱导固有免疫应答。本研究从大样本的病例-对照研究着手，深入探讨了相关TLRs基因的多态性与宫颈癌易感性的关系。结果表明，TLR7启动子区位点rs2897827和TLR8启动子区位点rs3761624多态性与中国汉族人群宫颈癌遗传易感性有关；其他所选TLRs潜在功能性多态性与宫颈癌发病风险无显著关联。本研究结果为宫颈癌高危人群的筛选提供了候选基因，具有重要的科学意义。