The Functional Analysis of Ovarian Cancer Susceptibility Locus 9p22.2

描述（由申请人提供）：由于我们无法在早期阶段发现卵巢癌，被诊断患有卵巢癌的女性的生存率很低。癌症易感性的预测标记对于识别有风险的个体很重要。BRCA1和BRCA2的种系突变是乳腺癌和卵巢癌的明确危险因素，但这些仅发生在卵巢癌病例的一小部分。有人提出，其余的卵巢癌病例是由低外显率癌症易感等位基因的组合引起的。全基因组关联研究（GWAS）最适合用于发现这些中等至低外显率的癌症易感等位基因，这些等位基因构成了该疾病的多基因成分。GWAS检测病例与对照组中单核苷酸多态性（snp）的频率，以发现与该疾病相关的遗传差异。已经发现了几个卵巢癌的候选基因座。然而，目前尚不清楚它们是如何增加疾病风险的。解决这个问题的最好方法是分析候选snp的功能。一个大型卵巢癌GWAS发现了一个与卵巢癌风险降低相关的SNP，最接近基因BNC2。与正常卵巢上皮细胞相比，BNC2在卵巢癌细胞中的表达水平也较低。BNC2在癌细胞中的低表达水平表明该蛋白具有肿瘤抑制作用，SNP可能增强该基因的功能或表达。BNC2有三对分离的C2H2锌指结构域，表明BNC2与DNA结合，可能具有转录调节剂的功能。我们将通过实现以下目标来验证BNC2作为一种转录调节剂作用于参与癌症启动的基因，从而影响癌症进展的假设：目的1：鉴定BNC2 zf识别的DNA序列。目的2：研究BNC2作为癌症相关基因转录调节因子的功能。目的3：研究GWAS中9p22位点的snp如何影响BNC2的功能。然后，我们将对BNC2的功能以及它如何影响卵巢癌风险有更深入的了解。这最终将使我们离预测、预防和治疗这种疾病更近一步。

DESCRIPTION (provided by applicant): Survival rates of women diagnosed with ovarian cancer are dismal due to our inability to identify ovarian cancer at early stages. Predictive markers for cancer predisposition would be important to identify individuals at risk. Germline mutations in BRCA1 and BRCA2 are well established risk factors for breast and ovarian cancer, yet these only occur in a small percentage of ovarian cancer cases. It has been proposed that the remaining ovarian cancer cases are caused by a combination of low penetrance cancer susceptibility alleles. Genome wide association studies (GWAS) are best used to find these moderate to low penetrance cancer susceptibility alleles that make up the polygeneic components of the disease. GWAS test the frequency of single nucleotide polymorphisms (SNPs) in cases versus controls to find the genetic differences that associate with the disease. Several candidate loci have been found for ovarian cancer. However it is unclear how they contribute to disease risk. The best way to solve this problem is to analyze the function of the candidate SNPs. A large ovarian cancer GWAS found a SNP associated with decreased risk of ovarian cancer nearest to the gene BNC2. BNC2 has also been shown to have low expression levels in ovarian cancer cells compared to normal ovarian epithelial cells. The low expression levels of BNC2 in cancer cells suggest that the protein acts as a tumor suppressor and the SNP may enhance function or expression of the gene. BNC2 has three separated pairs of C2H2 zinc finger domains suggesting that BNC2 binds to DNA and may function as a transcription regulator. We will test the hypothesis that BNC2 influences cancer progression by functioning as a transcriptional regulator acting on genes involved in cancer initiation by achieving the followin aims: Aim 1: To identify the DNA sequences recognized by the BNC2 ZFs. Aim 2: To investigate the function of BNC2 as a transcriptional regulator of cancer associated genes. Aim 3: To investigate how SNPs in the 9p22 locus identified in the GWAS impact the function of BNC2. We will then have a greater understanding of the function of BNC2 and how it influences ovarian cancer risk. This will ultimately lead us one step closer to predicting, preventing and treating the disease. PUBLIC HEALTH RELEVANCE: In most cases, by the time physicians detect ovarian cancer, it has already reached late stage disease and the chances of survival are slim. Therefore markers to identify women at risk of ovarian cancer would be beneficial. Genome-wide Association Studies have identified several loci that have a significant effect on ovarian cancer predisposition. Yet, the function of these Single Nucleotide Polymorphisms (SNPs) in these loci is unclear. The proposed project investigates the functional implications of a locus involved in predisposition to ovarian cancer. Understanding the mechanism of risk enhancement conferred by SNPs in this locus will aid in cancer prevention and treatment for patients with cancer predisposition.