The Odd-Even Effect of Polymorphic CA repeats in the 5' Regulatory Region of the

描述(申请人提供)：高渗透性基因(如BRCA1/2)的突变在所有高度家族性乳腺癌中只占不到一半，仅占所有乳腺癌的5%左右；这些基因在散发性乳腺癌中的作用尚不明确。因此，识别影响乳腺癌风险的新的多态胚系突变是重要的。表皮生长因子受体(EGFR)在直接参与乳腺癌发生发展的多个过程中发挥着重要作用。EGFR的表达水平是预测乳腺癌患者预后的主要指标之一。几项研究的结果表明，EGFR基因的胚系突变也可以调节乳腺癌的风险。EGFR基因最有趣的多态之一是位于该基因调控区的CA重复序列(Rs11568315)。我们的初步数据和之前公布的数据都表明，在所研究的四个种族群体中，奇数CA重复序列大量缺失：白人、亚洲人、拉美裔(墨西哥裔美国人)和非裔美国人。我们假设奇数等位基因(例如15、17、19)是有害的，会增加患乳腺癌的风险。我们将这一假说命名为“奇偶”假说。这个项目旨在检验奇偶假说。我们将在已经从1,500名乳腺癌患者和1,500名匹配的对照受试者身上收集的DNA样本中，对EGFR基因中的CA重复序列多态加上另外15个潜在功能的单核苷酸多态进行基因分型。与基因多态相关的风险将在已知流行病学风险因素的背景下进行估计，如年龄、乳腺癌家族史、月经初潮年龄、绝经年龄和第一次生育年龄。关于这些风险因素的信息也已经收集并可供分析。我们还将分析50个乳腺癌细胞系中EGFR的表达，并将其与CA重复序列的奇偶状态相关联。这项研究的结果将阐明EGFR基因的遗传多态在调节乳腺癌风险中的作用。EGFR在乳腺肿瘤中的表达是预测乳腺癌患者预后的重要指标。位于该基因调控区的多态CA重复序列(Rs11568315)是调节乳腺癌风险的最有前景的多态基因之一。我们注意到，在所有研究的四个民族中，奇数等位基因都存在巨大的缺失：高加索人、亚洲人、拉美人(墨西哥裔美国人)和非裔美国人。我们假设奇数等位基因出现的频率低于预期，因为它们是有害的，并增加了癌症(包括乳腺癌)的风险。这项研究项目的目标是通过确定EGFR基因中的奇数重复是否与乳腺癌风险增加相关来检验这一假说。为了实现这一目标，我们将比较病例和对照中奇数等位基因的频率以及来自EGFR基因的另外15个潜在功能单核苷酸多态的频率。我们还将分析50个乳腺癌细胞系中EGFR的表达，并将其与CA重复序列的奇偶状态相关联。这项研究的结果将提高我们对这一关键基因的遗传多态如何调节乳腺癌风险的理解。

DESCRIPTION (provided by applicant): Mutations in highly penetrant genes (such as BRCA1/2) are responsible for less than half of all strongly familial breast cancers and account for only about 5% of all breast cancers; no clear role for these genes in sporadic breast cancers has emerged. Therefore, identifying novel polymorphic germline mutations that affect the risk of breast cancer is important. Epidermal growth factor receptor (EGFR) plays an important role in several processes directly involved in the incidence and progression of breast cancer. The level of expression of EGFR is one of the major predictors of prognosis for breast cancer patients. The results of several studies have suggested that germline mutations in the EGFR gene can also modulate breast cancer risk. One of the most interesting polymorphisms in the EGFR gene is the polymorphic CA repeat (rs11568315) located in the gene's regulatory region. Both our preliminary data and previously published data indicate a massive deficit of odd-numbered CA repeats in four ethnic groups studied: whites, Asians , Hispanics (Mexican Americans), and African Americans. We hypothesized that odd-numbered alleles (e.g., 15, 17, 19) are detrimental and confer increased risk of breast cancer. We named this hypothesis the "odd-even" hypothesis. This project is designed to test the odd-even hypothesis. We will genotype the polymorphic CA repeat plus 15 additional potentially functional single-nucleotide polymorphisms in the EGFR gene in DNA samples already collected from 1,500 patients with breast cancer and 1,500 matched control subjects. The risk associated with the genetic polymorphisms will be estimated in the context of known epidemiologic risk factors such as age, family history of breast cancer, age at menarche, age at menopause, and age at first childbirth. Information on these risk factors is also already collected and available for the analysis. We will also analyze EGFR expression in 50 breast cancer cell lines and correlate it with the odd-even status of the CA repeat. The results of this study will elucidate the role of genetic polymorphisms in the EGFR gene in modulating the risk of breast cancer. EGFR expression in breast tumors is an important predictor of prognosis for breast cancer patients. A polymorphic CA repeat (rs11568315) located in the regulatory region of the gene is one of the most promising polymorphisms modulating the risk of breast cancer. We noticed that there is a massive deficit of odd-numbered alleles in all four ethnic groups studied: Caucasians, Asians, Hispanics (Mexican Americans), and African Americans. We hypothesized that odd-numbered alleles occur less frequently than expected because they are detrimental and confer an increased risk of cancer, including breast cancer. The goal of this research project is to test this hypothesis by determining whether odd-numbered repeats in the EGFR gene are associated with an increased risk of breast cancer. To achieve this goal, we will compare the frequencies of odd-numbered alleles in cases and controls and frequencies of 15 additional potentially functional single-nucleotide polymorphisms from the EGFR gene. We will also analyze EGFR expression in 50 breast cancer cell lines and correlate it with the odd-even status of the CA repeat. The results obtained in this study will improve our understanding of how genetic polymorphisms in this key gene modulate breast cancer risk.