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）：大肠癌（CRC）是美国癌症发病率和死亡率的重要原因。确定谁处于较高的风险中，在CRC中尤其重要，因为可获得可减少死亡的筛查测试。 CRC发展的风险既是遗传性和环境因素，这些因素和环境因素在所有人群之间并不统一。迄今为止，CRC遗传学领域主要集中在高加索人群上，而很少有研究包括非裔美国人（AA）患者。确定AAS中的危险因素是一个特别重要的目标，因为该人群中的发病率和死亡率都不像其他美国其他人口那样降低。在芝加哥大学，我们有独特的能力解决AAS中的遗传因素，因为我们组装了大型AA CRC病例对照系列。这项研究的主要目的是使用候选基因筛选方法鉴定CRC敏感性等位基因，并在AA CRC患者和对照组中进行关联测试。 CRC尤其适合候选基因研究，因为在遗传性CRC综合征中已经鉴定出与生物学相关的途径以及在腺瘤到癌序列中癌变的分析中。基本切除修复途径特别有趣，因为最近的工作阐明了与基因MYH突变相关的隐性息肉病综合征。因此，涉及该途径的基因是具有CRC敏感性等位基因的生物学上合理的候选者，但迄今为止尚未在AAS中充分识别或表征它们。我们的假设是，基础分离修复基因中的新敏感性等位基因有助于非裔美国人CRC发展的风险。为了检验这一假设，我们将使用高吞吐量异形分析分析筛选候选基础分离修复基因，并使用测序表征DNA变化（特定目标1）。为了控制我们混合的AA人群中的人口分层，我们将使用一组信息丰富的祖先信息标记来确定个体祖先的估计（具体目标2）。最后，我们将在一系列400个AA CRC病例和400个控制中鉴定出在候选基因筛选中鉴定出的假定的CRC敏感性等位基因，然后通过逻辑回归测试关联（特定目标3）。随着对个人风险和适当筛查的了解，大肠癌在很大程度上是可预防的疾病。我们研究的目的是更好地了解遗传因素，以增加风险，尤其是在这种癌症发病率最高和死亡的非裔美国人中。