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

描述（由申请人提供）：高渗透基因（如BRCA1/2）的突变导致不到一半的强家族性乳腺癌，仅占所有乳腺癌的5%左右；这些基因在散发性乳腺癌中没有明确的作用。因此，识别影响乳腺癌风险的新型多态生殖系突变是很重要的。表皮生长因子受体（EGFR）在乳腺癌的发生和发展过程中起着重要的作用。EGFR的表达水平是乳腺癌患者预后的主要预测指标之一。几项研究的结果表明，EGFR基因的种系突变也可以调节乳腺癌的风险。EGFR基因中最有趣的多态性之一是位于该基因调控区域的多态CA重复（rs11568315）。我们的初步数据和先前发表的数据都表明，在所研究的四个种族群体中：白人、亚洲人、西班牙裔（墨西哥裔美国人）和非洲裔美国人，奇数CA重复序列大量缺失。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。我们将这个假设命名为“奇偶”假设。这个项目旨在检验奇偶假设。我们将对从1500名乳腺癌患者和1500名匹配的对照组中收集的DNA样本中的多态CA重复加上15个额外的潜在功能的EGFR基因单核苷酸多态性进行基因分型。与遗传多态性相关的风险将在已知的流行病学风险因素的背景下进行评估，如年龄、乳腺癌家族史、月经初潮年龄、绝经年龄和首次分娩年龄。关于这些风险因素的信息也已收集并可供分析。我们还将分析50种乳腺癌细胞系中的EGFR表达，并将其与CA重复序列的奇偶状态相关联。本研究的结果将阐明EGFR基因遗传多态性在调节乳腺癌风险中的作用。EGFR在乳腺肿瘤中的表达是乳腺癌患者预后的重要预测因子。位于该基因调控区域的多态CA重复序列（rs11568315）是最有希望调节乳腺癌风险的多态性之一。我们注意到，在所研究的四个种族群体中：高加索人、亚洲人、西班牙人（墨西哥裔美国人）和非洲裔美国人，都存在大量的奇数等位基因缺失。我们假设奇数等位基因出现的频率比预期的要低，因为它们是有害的，会增加癌症的风险，包括乳腺癌。本研究项目的目标是通过确定EGFR基因的奇数重复是否与乳腺癌风险增加有关来验证这一假设。为了实现这一目标，我们将比较病例和对照组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性的频率。我们还将分析50种乳腺癌细胞系中的EGFR表达，并将其与CA重复序列的奇偶状态相关联。本研究获得的结果将提高我们对这一关键基因的遗传多态性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.