Genetic Association Study in African-American Colorectal Cancer Patients

非裔美国结直肠癌患者的遗传关联研究

• 批准号: 7531036
• 负责人: Sonia Kupfer
• 金额: $ 1.28万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531036
• 关键词: Address; African American; Alleles; Base Excision Repairs; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Carcinoma; Caucasians; Caucasoid Race; Cessation of life; Chicago; Colorectal Cancer; DNA; Development; Disease; Environmental Risk Factor; Genes; Genetic; Genotype; Goals; Heteroduplex Analysis; Incidence; Individual; Inherited; Logistic Regressions; Malignant Neoplasms; Morbidity - disease rate; Mutation; Pathway interactions; Patients; Population; Population Control; Predisposition; Purpose; Risk; Risk Factors; Screening procedure; Series; Stratification; Syndrome; Testing; Universities; Work; adenoma; cancer genetics; carcinogenesis; case control; colorectal cancer screening; gene repair; genetic association; improved; interest; mortality; novel; polyposis

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a significant cause of cancer morbidity and mortality in the US. Determining who is at higher risk is especially important in CRC because screening tests are available that are proven to reduce death. Risk of CRC development is due to both hereditary and environmental factors which are not uniformly shared between all populations. To date, the field of CRC genetics has focused largely on Caucasian populations, while few studies have included African-American (AA) patients. Determining risk factors in AAs is an especially important goal because both incidence and mortality in this population are not decreasing as they are in all other US populations. At the University of Chicago, we are uniquely equipped to address genetic factors in AAs because we have assembled a large AA CRC case-control series. The main purpose of this study is to identify CRC-susceptibility alleles using a candidate gene screen approach and test for association in AA CRC patients and controls. CRC is particularly amenable to candidate gene studies because biologically relevant pathways have been identified in hereditary CRC syndromes and in the analysis of carcinogenesis in the adenoma to carcinoma sequence. The base excision repair pathway is especially interesting because recent work has elucidated a recessive polyposis syndrome associated with mutations in the gene MYH. Thus, genes involved in this pathway are biologically plausible candidates for harboring CRC-susceptibility alleles, but they have not been adequately identified or characterized in AAs to date. Our hypothesis is that novel susceptibility alleles in base-excision repair genes contribute to risk of CRC development in African-Americans. To test this hypothesis, we will screen candidate base-excision repair genes using high throughput heteroduplex analysis and use sequencing to characterize DNA changes (Specific Aim 1). To control for population stratification in our admixed AA population, we will determine individual ancestry estimates using a set of high informative ancestry informative markers (Specific Aim 2). Finally, we will genotype our putative CRC-susceptibility alleles identified in our candidate gene screens in a series of 400 AA CRC cases and 400 controls and then test for association by logistic regression (Specific Aim 3). With improved understanding of individual risk and proper screening, colorectal cancer is largely a preventable disease. The goal of our study is to better understand hereditary factors that increase risk especially in African-Americans who have the highest incidence and death from this cancer.

描述（由申请人提供）：结直肠癌（CRC）是美国癌症发病率和死亡率的一个重要原因。确定谁的风险较高对于结直肠癌尤其重要，因为筛查测试已被证明可以减少死亡。结直肠癌发生的风险是由遗传和环境因素造成的，这些因素并非在所有人群中都相同。迄今为止，结直肠癌遗传学领域主要集中在白种人群体，而很少有研究包括非裔美国人 (AA) 患者。确定 AA 的危险因素是一个特别重要的目标，因为该人群的发病率和死亡率并没有像美国所有其他人群那样下降。在芝加哥大学，我们拥有独特的能力来解决 AA 中的遗传因素，因为我们已经建立了一个大型 AA CRC 病例对照系列。本研究的主要目的是使用候选基因筛选方法鉴定 CRC 易感性等位基因，并测试 AA CRC 患者和对照之间的关联。 CRC 特别适合候选基因研究，因为在遗传性 CRC 综合征和腺瘤到癌序列的癌发生分析中已经鉴定出生物学相关途径。碱基切除修复途径特别有趣，因为最近的工作阐明了与 MYH 基因突变相关的隐性息肉病综合征。因此，参与该途径的基因在生物学上是可能含有 CRC 易感性等位基因的候选基因，但迄今为止，它们尚未在 AA 中得到充分鉴定或表征。我们的假设是，碱基切除修复基因中的新易感性等位基因会增加非裔美国人患结直肠癌的风险。为了检验这一假设，我们将使用高通量异源双链分析筛选候选碱基切除修复基因，并使用测序来表征 DNA 变化（具体目标 1）。为了控制混合 AA 群体中的群体分层，我们将使用一组高信息祖先信息标记来确定个体祖先估计（具体目标 2）。最后，我们将对一系列 400 个 AA CRC 病例和 400 个对照的候选基因筛选中确定的假定 CRC 易感性等位基因进行基因分型，然后通过逻辑回归测试关联性（具体目标 3）。随着对个人风险了解的加深和适当的筛查，结直肠癌在很大程度上是一种可预防的疾病。我们研究的目的是更好地了解增加风险的遗传因素，尤其是非洲裔美国人，他们的癌症发病率和死亡率最高。