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识别卵巢癌，因此被诊断出患有卵巢癌的妇女的生存率很沮丧。癌症易感性的预测标记对于识别处于危险中的个体很重要。 BRCA1和BRCA2中的种系突变是乳腺癌和卵巢癌的良好危险因素，但这些突变仅发生在一小部分卵巢癌病例中。已经提出，其余的卵巢癌病例是由低渗透率癌易感性等位基因的组合引起的。基因组广泛的关联研究（GWAS）最好用于找到构成该疾病多功能成分的中等至低渗透率的癌症易感性等位基因。 GWAS在病例与对照组中测试单核苷酸多态性（SNP）的频率，以找到与该疾病相关的遗传差异。已经发现了几个候选基因群卵巢癌。但是，目前尚不清楚它们如何促进疾病风险。解决此问题的最佳方法是分析候选SNP的功能。大型卵巢癌GWA发现SNP与距离基因BNC2近的卵巢癌风险降低有关。与正常的卵巢上皮细胞相比，BNC2在卵巢癌细胞中的表达水平较低。 BNC2在癌细胞中的低表达水平表明该蛋白质充当肿瘤抑制因子，SNP可能会增强基因的功能或表达。 BNC2具有三个分离的C2H2锌指域，表明BNC2与DNA结合，并且可能充当转录调节剂。我们将检验以下假设：BNC2通过实现后续目标来影响参与癌症起源的基因的转录调节剂来影响癌症的进展：目标1：确定BNC2 ZFS认可的DNA序列。目标2：研究BNC2作为癌症相关基因的转录调节剂的功能。 AIM 3：研究GWA中鉴定的9P22基因座中的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。这最终将使我们更接近预测，防止和治疗疾病。