Genetic Association Study in African-American Colorectal Cancer Patients

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重要原因。确定谁的风险较高在结直肠癌中尤为重要，因为筛查测试已被证明可以减少死亡。儿童早期发育不良的风险是由于遗传和环境因素造成的，而这两种因素并不是由所有人口统一分担的。到目前为止，结直肠癌遗传学领域主要集中在高加索人群，而很少有研究包括非裔美国人(AA)患者。确定AAS的危险因素是一个特别重要的目标，因为这一人群的发病率和死亡率并没有像在所有其他美国人群中那样下降。在芝加哥大学，我们拥有独特的设备来解决再生障碍性贫血的遗传因素，因为我们已经组装了大型再生障碍性贫血CRC病例对照系列。这项研究的主要目的是利用候选基因筛选方法识别CRC易感等位基因，并测试AA CRC患者和对照之间的相关性。结直肠癌特别适合于候选基因研究，因为在遗传性结直肠癌综合征和腺瘤到癌序列的致癌分析中，已经确定了生物学相关的途径。碱基切除修复途径特别有趣，因为最近的工作已经阐明了一种与MYH基因突变相关的隐性息肉综合征。因此，这一途径中涉及的基因是携带CRC易感等位基因的生物学上可信的候选基因，但到目前为止，它们在AAS中还没有得到充分的鉴定或表征。我们的假设是，碱基切除修复基因中的新易感等位基因与非裔美国人发生结直肠癌的风险有关。为了验证这一假设，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(特定目标1)。为了控制混合AA种群中的种群分层，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估计(特定目标2)。最后，我们将在400例AA结直肠癌病例和400名对照中对我们候选基因筛查中确定的假定的CRC易感等位基因进行基因分型，然后通过Logistic回归检验关联性(特定目标3)。随着对个体风险的更好了解和适当的筛查，结直肠癌在很大程度上是一种可以预防的疾病。我们研究的目标是更好地了解增加风险的遗传因素，特别是在这种癌症的发病率和死亡率最高的非裔美国人中。

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.