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

卵巢癌易感位点9p22.2的功能分析

• 批准号: 8928394
• 负责人: Melissa A. Buckley
• 金额: $ 3.3万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928394
• 关键词: 9p22; 9p22.2; Affect; Alleles; BRCA1 Mutation; BRCA1 gene; BRCA2 gene; Bachelor' s Degree; Binding; Binding Sites; Biochemistry; Bioinformatics; Biological Assay; Biology; Breast Cancer Risk Factor; C2H2 Zinc Finger; Cancer Biology; Cancer Patient; Cells; Cellular biology; Computer Simulation; DNA; DNA Binding; DNA Sequence; Data; Development; Developmental Biology; Diagnosis; Disease; Doctor of Philosophy; Electrophoretic Mobility Shift Assay; Epithelial Cells; Epithelial ovarian cancer; Experimental Designs; First Degree Relative; Frequencies; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Genotype; Germ-Line Mutation; Immunoprecipitation; Individual; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Molecular Biology; Molecular Profiling; Normal Cell; One-Step dentin bonding system; Ovarian; Patients; Penetrance; Pharmacologic Substance; Physicians; Play; Positioning Attribute; Predisposition; Problem Solving; Proteins; Proteomics; Recombinant Proteins; Risk; Role; Single Nucleotide Polymorphism; Site-Directed Mutagenesis; Staging; Survival Rate; Techniques; Testing; Time; Tissues; Transcriptional Regulation; Transfection; Tumor Suppression; Tumor Suppressor Proteins; Validation; Woman; Work; Zinc Fingers; base; basonuclin; cancer cell; cancer genome; cancer initiation; cancer prevention; cancer risk; cancer therapy; case control; chromatin immunoprecipitation; disorder risk; experience; gene function; genome wide association study; mRNA Expression; malignant breast neoplasm; novel; prevent; programs; reproductive; tumor progression

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.

描述（由申请人提供）：由于我们无法在早期阶段识别卵巢癌，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高危个体非常重要。 BRCA1 和 BRCA2 的种系突变是乳腺癌和卵巢癌的明确危险因素，但这些突变仅发生在一小部分卵巢癌病例中。有人提出，其余卵巢癌病例是由低外显率癌症易感性等位基因组合引起的。全基因组关联研究 (GWAS) 最适合发现这些构成该疾病多基因成分的中度至低外显率癌症易感性等位基因。 GWAS 测试病例与对照中单核苷酸多态性 (SNP) 的频率，以发现与疾病相关的遗传差异。已发现卵巢癌的几个候选基因座。然而，尚不清楚它们如何增加疾病风险。解决这个问题的最好方法是分析候选SNP的功能。一项大型卵巢癌 GWAS 发现了与 BNC2 基因最接近的与卵巢癌风险降低相关的 SNP。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充当肿瘤抑制因子，并且 SNP 可能增强该基因的功能或表达。 BNC2 具有三对独立的 C2H2 锌指结构域，表明 BNC2 与 DNA 结合并可能充当转录调节因子。我们将测试以下假设：BNC2 通过作为转录调节因子作用于癌症起始相关基因，从而影响癌症进展，实现以下目标： 目标 1：鉴定 BNC2 ZF 识别的 DNA 序列。目标 2：研究 BNC2 作为癌症相关基因转录调节因子的功能。目标 3：研究 GWAS 中确定的 9p22 位点中的 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。这最终将使我们在预测、预防和治疗这种疾病方面更近一步。