Differential gene expression in IGFs genes and the risk of breast cancer

IGF基因的差异基因表达与乳腺癌风险

• 批准号: 7458622
• 负责人: Yuan C Ding
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-11-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458622
• 关键词: Affect; Alleles; Apoptosis; Biological Assay; Blood Tests; Body Weight; Cancer Cell Growth; Cell Line; Cell Proliferation; Chromosomes; Clinical Research; Complementary DNA; Complex; Conditioned Culture Media; DNA; Data; Development; Diagnostic tests; Disease; Enzyme-Linked Immunosorbent Assay; Exhibits; Future; Gene Expression; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Genotype; Haplotypes; Heterozygote; IGF1 gene; IGFBP3 gene; Individual; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Investigation; Knowledge; Lead; Malignant Neoplasms; Measures; Messenger RNA; Methods; Missense Mutation; Patients; Play; Population; Primer Extension; Principal Investigator; Proteins; RNA; Range; Relative (related person); Risk; Role; Sampling; Serum; Signal Pathway; Single Nucleotide Polymorphism; Somatomedins; Splice-Site Mutation; System; Techniques; Testing; Tissue-Specific Gene Expression; Variant; Work; base; cancer risk; design; diet and exercise; disorder risk; genetic epidemiology; mRNA Expression; malignant breast neoplasm; novel diagnostics; programs; protein function; research study

DESCRIPTION (provided by applicant): Investigations of the genetic etiology of cancer have mainly focused on sequence variants that alter protein function (protein quality) such as truncating mutations, missense substitutions, and splice junction mutations. However, recent studies suggest that, for complex diseases, milder changes in protein quantity may be more important than radical changes in the protein quality. Increasing evidence has shown that regulatory polymorphisms that affect gene expression abundance can modify disease risk. The insulin-like growth factor (IGF) system plays an important role in regulating cellular proliferation and apoptosis. Deregulation of the IGF system leads to cancer cell growth and survival. Converging data from genetic epidemiology and clinical studies provide strong evidence that high circulating levels of IGF1 protein and low circulating levels of IGFBP3 protein in serum significantly predict increased risks of breast cancer. Although IGF1 and IGFBP3 circulating levels are associated with increased risk of breast cancer at the population level, individual risk cannot be easily assigned by directly measuring the protein concentration in serum, because the normal IGF1 and IGFBP3 protein ranges are wide and circulating levels are influenced by several personal factors including diet, exercise, and body weight. Limited data also suggest that both IGF1 and IGFBP3 exhibit allele-specific gene expression (ASGE), which is usually controlled by regulatory polymorphisms. Therefore, the elucidation of regulatory polymorphisms responsible for increasing the risk of breast cancer and development of simple DNA-based assays may allow us to accurately identify healthy individuals who are at high risk of breast cancer in the future. Hypothesis: Regulatory polymorphisms in genes in the IGF signaling pathway, which control allele-specific gene expression (ASGE), affect risk of developing breast cancer. Specifically, we will investigate the following hypotheses: 1). the inter-individual variation in IGF1 and IGFBP3 protein levels are due to ASGE in these genes; 2). Specific haplotype(s) in IGF1 gene are correlated with over-expression of IGF1 and specific haplotype(s) in IGFBP3 correlated with reduced expression of IGFBP3. This resubmission is focused on ASGE in the IGF and IGFBP3 genes. In this application, we will identify ASGE in cell lines for these two genes, by recently developed techniques, in Aim 1, determine the haplotypes, correlated to ASGE, through re- sequencing in Aim 2, and then test if the ASGE in mRNA level results in alterations in protein level in Aim 3. We will identify haplotypes responsible for ASGE and inter-individual variation in protein levels of IGF1 and IGFBP3. This approach will lead to a new diagnostic test in which ASGE can be assayed with a DNA-based blood test. In future work, we will then determine if there is an association with breast cancer risk, as well as test for ASGE in additional genes. If there is an association with breast cancer, this test could be a valuable predictive marker of an individual's risk for breast cancer. The knowledge could then be used to assist clinicians and their patients to more accurately assess breast cancer risk and help in designing effective preventative strategies.

描述(由申请人提供)： 对癌症遗传病因学的研究主要集中在改变蛋白质功能(蛋白质质量)的序列变异上，如截断突变、错义替换和剪接连接突变。然而，最近的研究表明，对于复杂的疾病，蛋白质数量的轻微变化可能比蛋白质质量的剧烈变化更重要。越来越多的证据表明，影响基因表达丰度的调控多态可以改变疾病风险。胰岛素样生长因子(IGF)系统在调节细胞增殖和凋亡方面发挥着重要作用。解除对IGF系统的调控会导致癌细胞的生长和存活。来自遗传流行病学和临床研究的综合数据提供了强有力的证据，表明血清中循环中IGF1蛋白的高水平和IGFBP3蛋白的低循环水平显著地预测乳腺癌风险的增加。虽然IGF1和IGFBP3的循环水平与人群患乳腺癌风险的增加有关，但通过直接测量血清中的蛋白质浓度很难确定个体的风险，因为正常的IGF1和IGFBP3的蛋白质范围很广，而且循环水平受到包括饮食、锻炼和体重在内的几个个人因素的影响。有限的数据也表明IGF1和IGFBP3都表现出等位基因特异性的基因表达(ASGE)，这通常是由调节基因的多态控制的。因此，阐明导致乳腺癌风险增加的调节基因多态以及发展简单的基于DNA的检测方法可能使我们能够准确地识别未来乳腺癌高危健康个体。假设：IGF信号通路中控制等位基因表达(ASGE)的基因的调节性多态影响乳腺癌的发生风险。具体来说，我们将研究以下假设：1)。IGF1和IGFBP3蛋白水平的个体间差异是由于这些基因中的ASGE所致；IGF1基因的特异性单倍型(S)与IGF1的过度表达相关，IGFBP3的特异性单倍型(S)与IGFBP3的表达下调相关。这次重新提交的重点是IGF和IGFBP3基因中的ASGE。在这一应用中，我们将通过最新发展的技术，在AIM 1中鉴定这两个基因在细胞系中的ASGE，通过在AIM 2中的重新测序来确定与ASGE相关的单倍型，然后测试ASGE在mRNA水平是否会导致AIM 3中蛋白质水平的变化。我们将确定导致ASGE以及IGF1和IGFBP3蛋白质水平个体间差异的单倍型。这一方法将导致一种新的诊断测试，其中ASGE可以通过基于DNA的血液测试进行检测。在未来的工作中，我们将确定这是否与乳腺癌风险有关，以及测试其他基因中的ASGE。如果与乳腺癌有关联，这项测试可能是个人患乳腺癌风险的一个有价值的预测标志。然后，这些知识可以用来帮助临床医生和他们的患者更准确地评估乳腺癌风险，并帮助设计有效的预防策略。