宫颈癌遗传易感SNP位点相关致癌基因的筛选及功能验证

Cervical cancer is the second most common malignant tumour in the world in women between the ages of 15 and 44 years old. Human Papillomavirus (HPV) infection is a necessary cause of invasive cervical cancer, in additionally, long-term use of oral contraceptives, high parity, and smoking are considered to be cofactors. But HPV infection is not a sufficient condition of the progression of cervical cancer, the genetic background of the host also played an important role in the tumorigenesis. Our team has found 4 independently associated SNPs of cervical cancer through the Genome-Wide Association Study (GWAS). Based on this evidence, this study will screen the regulator genes of the 4 SNPs, analyze the interaction between the HPV integration and these regulator genes. The In vivo experiments and in vitro experiments will be used to study the effects of these regulator genes in the tumorigenesis. We hope our findings will find some new genes related to the progression of cervical cancer，and provide new insights into the genetic etiology of cervical cancer.

宫颈癌是世界范围内15-44岁女性第二大恶性肿瘤。宫颈癌发病的高危因素包括人乳头瘤病毒(Human Papillomavirus, HPV)感染、早婚早育、吸烟等，其中HPV感染为最主要因素。但HPV感染并不是宫颈癌发生的充分条件，宿主的遗传背景也扮演了重要角色。本项目组前期通过汉族人群宫颈癌GWAS项目发现了4个与宫颈癌发病独立相关的位点。在此基础上，本项目拟通过临床标本初步筛选验证以上4个SNP位点相关的调控基因，分析HPV整合状态与相关基因的交互作用，并利用体外实验和体内实验多层面验证相关基因在肿瘤发生进程中的影响作用。我们希望通过次研究，找到新的与宫颈癌发生相关的基因，为宫颈癌遗传学病因的探索提供新的视野。

宫颈癌是女性第二大恶性肿瘤。HPV感染虽然是宫颈癌发生的重要危险因素，但并不是宫颈癌发病的充分条件，遗传学因素也可能和肿瘤的发生相关。本项目组前期通过汉族人群宫颈癌GWAS研究筛选出4个与宫颈癌发生独立相关的SNP位点。本研究利用通路分析筛选出6个相关基因，并初步验证其可能与宫颈癌的遗传易感性相关。同时我们进一步挖掘数据，结合相关病例的临床化疗敏感性特征，交叉分析临床发病高危因素、预后及遗传位点检测结果筛选出与化疗敏感相关位点。进一步通过后续两轮共370例临床样本验证试验，发现rs6812281 (rs6812281, per allele OR = 2.37, P = 9.0 × 10−9)、rs4590782(10q26.2, P = 1.59 × 10−5, per allele OR = 0.48)、rs1742101 (14q32.11, P = 7.11 × 10−6, per allele OR = 0.52)以及rs1364121(16q23.3, P = 3.15 × 10−6, per allele OR = 1.98)这4个SNP位点与宫颈癌化疗敏感性相关，可能影响宫颈癌患者预后。本研究结果为宫颈癌遗传学病因的探索提供新的视野。

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