Adding Hispanics to Ongoing GWAS in Colorectal Cancer

描述(由申请人提供)：结直肠癌全基因组关联研究(GWAS)有助于在非西班牙裔(NH)-白人人群中确定一些常见的易感基因，NCI的优先事项是将GWAS的研究结果推广到其他人群，以解决癌症易感性的种族/民族差异。目前，GWA正在对NH-白人、日本人和非裔美国人中的CRC进行研究。我们建议进行一项补充研究，以解决拉美裔美国人的这一关键研究领域。拉美裔是美国增长最快的种族人口，在癌症遗传易感性方面，他们的研究在很大程度上是不够的。各族裔/种族群体在结直肠癌的发病率、存活率和死亡率方面存在明显差异。与NH-白人相比，拉美裔人通常在较年轻的时候出现结直肠癌，并且IV期肿瘤或转移性疾病的发生率显著更高。我们建议在美国国立卫生研究院资助的现有资源、结肠癌家庭登记(Colon CFR)和多种族队列研究(MEC)的基础上，在拉美裔美国人中开展大规模、具有成本效益的、以人口为基础的全球癌症研究。我们计划招募2500名西班牙裔男性和女性，从2010年1月到2013年10月，通过加州的癌症登记被诊断出患有结直肠癌。风险因素/饮食问卷、病理报告、Oragene口腔样本(用于基因分型)和肿瘤块(用于MSI测试)将使用Colon CFR/MEC开发的方法收集。儿童权利委员会的儿童权利公约案例(目前为473例；预计年底为600例)也将包括在内。参加MEC其他GWA研究(n=3,900，U01HG004726，海曼)的无CRC诊断的基于人口的西班牙裔个人将被用作对照。我们将使用Illumina 1M阵列对所有3100例病例进行基因分型，并使用在3900名对照中收集的可用的基因分型和流行病学数据。我们的统计分析将包括：单SNP和单倍型效应，基因-环境交互作用和MSI的异质性，肿瘤亚型和结直肠癌家族史。我们将在第二阶段使用墨西哥的CRC病例和对照(1,000个病例和1,000个对照，欧盟FP7资助，Chibcha，Carvajal-Carmona/Tomlinson)复制结果。我们还将通过利用GWA关于NH-白人(2,142例，1,909例对照，U01 CA122839，Casey)、(4,000例，6,000例NH-White对照，UK-Chibcha，Tomlinson)、哥伦比亚人(2,000例病例和2,000例对照，Chibcha)、日本人(1,000例病例和1,000例对照，R01CA126895，Le Marchand)和非裔美国人(1,500例和1,500对照，R01CA126895，Le Marchand)的数据，检查按种族/种族进行的风险估计的异质性。我们将在我们的主要和联合分析中在几个拉美裔人群中复制重要的SNPs(注：由欧盟或NIH资助的数据收集但不是Gwas的研究)，包括：800名波多黎各人、2,000名巴西人、2,000名阿根廷人和3,000名西班牙人/葡萄牙人，以评估研究结果的概括性。这项研究将产生重大影响，解决与儿童权利公约遗传易感性有关的种族/族裔差异这一关键问题，并将通过提供缺乏的遗传数据和生物标本资源，使拉美裔美国人能够进一步增长和投资于研究。

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) of colorectal cancer (CRC) have been instrumental in identifying a number of common susceptibility loci in Non Hispanic (NH)-White populations and a NCI priority is to extend GWAS findings to other populations to address racial/ethnic disparities in cancer susceptibility. Currently, GWA studies of CRC in NH-Whites, Japanese and African-Americans are ongoing. We propose a complementary study to address this critical research area in Hispanics. Hispanics represent the fastest growing ethnic population in the U.S. and have been largely understudied in terms of genetic susceptibility to cancer. There are noted differences in incidence, survival and mortality in CRC by ethnic/racial groups. Hispanics often present with CRC at a younger age and have a significantly greater incidence of stage IV tumors or metastatic disease compared to NH-Whites. We propose to conduct a large, cost-efficient, population-based GWAS in Hispanics by building upon existing NIH-funded resources, the Colon Cancer Family Registry (Colon CFR) and the Multiethnic Cohort Study (MEC). We plan to recruit 2,500 Hispanic men and women diagnosed with CRC between 01/2010 to 10/2013 using cancer registries in California. Risk factor/diet questionnaires, pathology reports, Oragene buccal samples (for genotyping) and tumor blocks (for MSI testing) will be collected using methodologies developed in the Colon CFR/MEC. Cases of CRC in the MEC (currently 473; anticipated 600 at end) will also be included. Population-based Hispanic individuals without a diagnosis of CRC participating in other GWA studies in the MEC (n=3,900, U01HG004726, Haiman) will be used as controls. We will genotype all 3,100 cases using the Illumina 1M array and use available genotype and epidemiologic data collected on 3,900 controls. Our statistical analyses will include: single-SNP and haplotype effects, gene-environment interactions and heterogeneity by MSI, tumor subtype and family history of CRC. We will replicate findings in a second-stage using CRC cases and controls from Mexico (1,000 cases and 1,000 controls, EU FP7 funding, CHIBCHA, Carvajal-Carmona/Tomlinson). We will also examine heterogeneity of the risk estimates by ethnicity/race by leveraging GWA data on NH-Whites (2,142 cases, 1,909 controls, U01 CA122839, Casey), (4,000 cases, 6,000 NH-White controls, UK-CHIBCHA, Tomlinson), Colombians (2,000 cases and 2,000 controls, CHIBCHA), Japanese (1,000 cases and 1,000 controls) and African-Americans (1,500 cases and 1,500 controls, R01CA126895, Le Marchand). We will genotype replicated significant SNPs in our main and combined analysis in several Hispanic populations (note: studies funded by EU or NIH for data collection but not GWAS) including: 800 Puerto Ricans, 2,000 Brazilians, 2,000 Argentineans and 3,000 Spanish/Portuguese to assess generalizability of findings. This study will have a high impact by addressing the key question of racial/ethnic disparities related to genetic susceptibility to CRC, and will enable further growth and investment into research among Hispanics by providing a resource of genetic data and biospecimens, which is lacking.