染色体12q14.2区多态性与卵巢癌易感性关系及功能研究

Ovarian cancer is a complex polygenic disease in which genetic factors play an important role.We took the lead in a three-stage GWAS in the Han Chinese population for epithelial ovarian cancer (EOC) susceptibility, aiming to find the Chinese-specific genetic susceptibility information.On the basis of the GWAS, we find that a new loci rs11175194 at 12q14.2 is an ovarian cancer-related risk factor in the Han Chinese population. Rs11175194 locates in the first intron of SRGAP1. The experimental data show that different genotype is associated with its gene expression,and higher expression suggests poor prognosis. Therefore the susceptibility loci are very important that may become a potential maker for high-risk screening, diagnosis and treatment of ovarian cancer.By re-sequencing combined with fine-scale mapping of the loci, we propose to screen out linkage disequilibrium loci and detect their frequency distribution by large population-based case-control study. Then we analyze the interaction between SNP genotypes and environmental factors and perform functional experiments of 3-5 selected loci and its related gene. At the same time, through comparing our data with the data from TCGA, we can find out the similarities and differences between different ethnicities in east and west. Our project will help elucidate the etiology and pathogenesis of ovarian cancer, screen out high-risk susceptible population and provide new basis for early diagnosis and prognosis prediction of ovarian cancer, which, in total may improve the early detection rate and reduce the mortality of ovarian cancer.

卵巢癌是复杂的多基因疾病，遗传因素发挥重要作用。本项目组牵头在国内开展了中国汉族女性上皮源性卵巢癌GWAS研究，旨在发现国人特有的遗传易感信息。在此基础上发现位于12q14.2区的rs11175194位点与国人卵巢癌发病风险相关，该位点位于SRGAP1基因内含子上，不同基因型与该基因表达相关，且表达高预后差，提示此易感区域非常重要，可能成为潜在的卵巢癌高危筛查、诊断及治疗靶点。本研究拟采用测序方法对12q14.2区域进行精细定位，筛选高连锁位点，以大样本病例对照方法检测连锁位点频率分布，分析SNPs基因型与环境因素的交互作用，预测该区域卵巢癌易感位点功能，选取1-2个位点及相关基因进行功能探索，同时结合美国TCGA数据进行验证，比较东西方不同种族之间的共同点和差异，为阐明卵巢癌的病因及发生发展机制，筛选高危易感人群，开展早期诊断及预后预测提供新依据，为提高卵巢癌早诊率降低死亡率提供参考。

卵巢癌是女性生殖器官常见的恶性肿瘤之一，死亡率居女性生殖系统肿瘤之首，鉴于没有切实有效早诊方法，导致临床上70％患者确诊时已是晚期，5年生存率不足30％。卵巢癌发病原因除流行病学提示的宏观因素外，遗传因素也发挥重要作用。.在前期在中国汉族女性上皮源性卵巢癌GWAS研究基础上，发现rs11175194位点与国人卵巢癌易感性相关，进而开展易感性位点的功能研究。该位点位于SRGAP1基因intro1上，携带“G”基因型患者SRGAP1表达高于“A”基因型；Transfac预测发现转录因子NR1H4可与rs11175194位点“G”结合；TCGA（r=0.154）、GEO（r=0.393）和天津（r=0.467）数据均显示NR1H4与SRGAP1基因表达呈正相关，p<0.05；荧光素酶报告基因和Chip实验及测序证实“G”基因型有增强子作用，可增加SRGAP1基因表达。在SKOV3和OVCA432细胞中进行细胞学实验，与对照相比过表达SRGAP1基因可以导致细胞增殖和克隆化形成增加，但不改变细胞的迁移和侵袭能力。天津样本中SRGAP1基因表达和患者预后相关，其结果在TCGA数据中得到验证，同时表达谱芯片结果显示SRGAP1基因表达癌组织高于配对癌旁组织1.68倍，据此进行药物敏感性实验发现过表达SRGAP1基因可以提高卵巢癌细胞系对化疗药物紫杉醇和表柔比星的抗性。.对rs11175194高LD区域采用二代测序方法进行精确作图，依据SNP筛选标准选择12个SNP在1099例病例和1591例对照中验证，发现rs11175195和rs67799338与卵巢癌易感性相关，经不同基因型SRGAP1表达差异和Transfac预测发现rs67799338“C”基因型可与转录因子Ref-1、Sp1和AP1-1结合。.本项目为阐明卵巢癌的病因、早诊及预后预测提供新依据，为开展后GWAS研究提供一种模式。

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