染色体9q22.33区多态性与卵巢癌易感性关系及功能研究

Ovarian cancer is a complex polygenic disorder for which genetic factors play a significant role in disease etiology. We recently conducted a three-stage GWAS in Han Chinese population of epithelial ovarian cancer (EOC) and identified a new locus rs1413299 at 9q22.33 was the top sinal SNP. SNP rs1413299 is located in intron 6 of COL15A1 and 105kb uptream of exon 1 of TGFBR1. COL15A1 encodes alpha chain of type XV collagen at 9q22.33, a member of the FACIT (fibril-associated collagens with interrupted helices) collagen family and was found to suppress tumorigenesis. TGFBR1 is a central propagator of the TGF-β (Transforming growth factor-β) signaling pathway that is an important regulator of several important biological processes, including cell proliferation, differentiation, migration, apoptosis, and matrix accumulation.The gene expression data from The Cancer Genome Atlas(TCGA) suggested that COL15A1 gene expression level was significantly different between tumours and normal tissues, and that the expression level of TGFBR1 was significantly associated with patient survival. Thus, we hypothesized that rs1413299 variants have a different pattern of downstream genes and eventually infuence the risk of ovarian cancer. We will perform a three stage study. In stage I, we have been conducted fine-mapping of the ovarian cancer susceptibility region 9q22.33 and we will select the SNPs are High LD with rs1413299. In stage 2, we will investigate the association between the SNPs and ovarian cancer in large population. Finally, we will select the possible functional SNPs and perform functional studies in ovarian cancer cell lines to reveal the role of SNPs in gene expression and carcinogenesis. It’s facilitating to clarify the ovarian cancer etiology and pathogenesis, as well as screening of susceptible populations. More importantly, the significant findings of this study may provide a clue to early diagnosis and individual prevention measures 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。本课题组牵头在国内开展了中国汉族女性上皮源性卵巢癌GWAS研究并且已发表。我们发现了2个国人特有的卵巢癌易感位点，其中具有最显著意义的是位于9q22.33区的rs1413299位点。该SNP位于COL15A1基因内含子6上，TGFBR1基因的上游105kb上。美国TCGA数据显示COL15A1基因表达在卵巢癌肿瘤组织和癌旁正常组织间有差异，且TGFBR1表达高预后差。因此，本课题将采用三个阶段进行，首先在第一阶段采用精细扫描作图后，进行连锁关联分析，找出此区域中与rs1413299有高连锁的SNPs；然后，采用病例对照研究方法进行关联分析，找出与卵巢癌易感性相关的SNPs；最后，利用计算机软件预测筛选有调控意义的功能SNP位点，进行细胞学功能研究。本课题为阐明卵巢癌的发生机制、筛选易感人群、开展早期诊断及个体预防提供基础，具有深远的临床意义。

卵巢癌是复杂的多基因疾病，遗传因素发挥重要作用。本课题组前期的中国汉族女性上皮源性卵巢癌GWAS研究中，发现了2个国人特有的卵巢癌易感位点，其中具有最显著意义的是位于9q22.33区的rs1413299位点，我们对此区域进行重测序，筛选出此区域中与rs1413299有高连锁的21个SNP位点；然后在1099例卵巢癌病例和1591例健康对照，使用Sequenom iPlex 和WaferGen平台进行了21个SNP位点的基因分型，通过统计分析筛选出5个与卵巢癌易感性相关的SNP位点；选取101例卵巢癌肿瘤组织，采用real-time 实时定量PCR 方法对SNPs 位点相关基因的mRNA 表达进行检测。比较不同SNPs 基因型mRNA 表达的差异，发现2个SNP的基因型（rs7027650和rs1889268）跟Col15A1表达具有相关性。最后，通过功能预测软件预测SNP功能，发现rs7027650可能是9q22.33区域的功能SNP，凝胶迁移滞后实验发现了rs7027650的A基因型相较于T基因型有明显的结合集合条带。本研究为卵巢癌病因学研究以及探索新的生物标志物提供可能的依据。

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