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

多态性 CA 重复序列在 5 调控区的奇偶效应

基本信息

批准号：
7500858
负责人：
IVAN P GORLOV
金额：
$ 7.7万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-24 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7500858
关键词：
Accounting Affect African American Age Age at Menarche Alleles Asians BRCA2 gene Breast Cancer Cell Breast Cancer Risk Factor Breast Cancer Treatment Cancer Etiology Cancer Patient Cancer cell line Caucasians Caucasoid Race Cell Line Cessation of life Childbirth Cities Clinical DNA Data Decompression Sickness Development Diagnosis Dinucleoside Phosphates Dinucleotide Repeats Disease Epidemiologic Factors Epidemiology Epidermal Growth Factor Receptor Ethnic group Family history of Frequencies Gene Frequency Genes Genetic Genetic Polymorphism Genetic Variation Genotype Germ-Line Mutation Goals Hereditary Breast Carcinoma Hispanics Human Genome Incidence Individual Joints Link Mammary Neoplasms Menopause Mexican Americans Molecular Target Mutation Names Nucleic Acid Regulatory Sequences Numbers Oklahoma PTEN gene Patients Pattern Penetrance Pharmaceutical Preparations Play Polymerase Chain Reaction Prevention strategy Process Production Publishing Range Research Project Grants Risk Risk Factors Role Sampling Single Nucleotide Polymorphism Statistical Models Susceptibility Gene TP53 gene Testing United States University of Texas M D Anderson Cancer Center Work c-erbB-1 Proto-Oncogenes cancer risk case control design disorder risk genetic variant improved interest malignant breast neoplasm novel outcome forecast receptor expression

项目摘要

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.

描述（由申请人提供）：高度外显基因（如BRCA 1/2）的突变与所有强家族性乳腺癌中不到一半有关，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清楚。因此，鉴定影响乳腺癌风险的新的多态性生殖系突变是重要的。表皮生长因子受体（EGFR）在乳腺癌的发生和发展中起着重要的作用。EGFR的表达水平是乳腺癌患者预后的主要预测因子之一。几项研究的结果表明，EGFR基因的生殖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基因调控区的多态性CA重复序列（rs 11568315）。我们的初步数据和先前发表的数据都表明，在研究的四个种族群体中，奇数CA重复序列存在大量缺陷：白人，亚洲人，西班牙裔（墨西哥裔美国人）和非洲裔美国人。我们假设奇数等位基因（例如，15，17，19）是有害的，并赋予乳腺癌的风险增加。我们将这个假说命名为“奇偶”假说。该项目旨在测试奇偶假设。我们将对从1,500例乳腺癌患者和1,500例匹配的对照受试者中收集的DNA样本中EGFR基因的多态性CA重复序列加上15个额外的潜在功能性单核苷酸多态性进行基因分型。将在已知流行病学风险因素（如年龄、乳腺癌家族史、初潮年龄、绝经年龄和首次分娩年龄）的背景下估计与遗传多态性相关的风险。关于这些风险因素的资料也已经收集，可供分析之用。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。本研究的结果将阐明EGFR基因的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。位于该基因调控区的多态性CA重复序列（rs 11568315）是调节乳腺癌风险的最有前途的多态性之一。我们注意到，在研究的所有四个种族群体中，奇数等位基因都存在巨大缺陷：高加索人、亚洲人、西班牙裔（墨西哥裔美国人）和非裔美国人。我们假设奇数等位基因的出现频率低于预期，因为它们是有害的，并增加患癌症的风险，包括乳腺癌。该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验证这一假设。为了实现这一目标，我们将比较病例组和对照组中奇数等位基因的频率以及EGFR基因15个额外的潜在功能性单核苷酸多态性的频率。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。本研究获得的结果将提高我们对这个关键基因的遗传多态性如何调节乳腺癌风险的理解。