Adding Hispanics to Ongoing GWAS in Colorectal Cancer

描述（由申请人提供）：结直肠癌（CRC）的全基因组关联研究（GWAS）有助于确定非西班牙裔（NH）白人人群中许多常见的易感位点，NCI的优先事项是将GWAS研究结果扩展到其他人群，以解决癌症易感性的种族/民族差异。目前，nh -白人、日本人和非洲裔美国人的结直肠癌的GWA研究正在进行中。我们提出一项补充研究，以解决西班牙裔人这一关键研究领域。拉美裔是美国人口增长最快的族群，在癌症的遗传易感性方面，他们的研究在很大程度上还不够充分。不同民族/种族的CRC发病率、生存率和死亡率存在显著差异。与非裔白人相比，西班牙裔经常在年轻时出现结直肠癌，并且IV期肿瘤或转移性疾病的发生率明显更高。我们建议在美国国立卫生研究院资助的现有资源、结肠癌家庭登记处（Colon CFR）和多民族队列研究（MEC）的基础上，在西班牙裔人群中开展一项大规模、成本效益高、基于人群的GWAS。我们计划在2010年1月至2013年10月期间在加州癌症登记处招募2500名诊断为结直肠癌的西班牙裔男性和女性。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检测）将使用结肠CFR/MEC开发的方法收集。MEC的CRC病例（目前为473例，预计最终为600例）也将包括在内。在MEC参加其他GWA研究（n=3,900, U01HG004726, Haiman）的未诊断为结直肠癌的基于人群的西班牙裔个体将被用作对照。我们将使用Illumina 1M阵列对所有3100例病例进行基因分型，并使用收集到的3900例对照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-环境相互作用和MSI异质性，肿瘤亚型和CRC家族史。我们将在第二阶段使用来自墨西哥的结直肠癌病例和对照（1000例和1000例对照，欧盟FP7资助，CHIBCHA, Carvajal-Carmona/Tomlinson）重复研究结果。我们还将通过利用GWA数据对NH-White（2142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例和2,000例对照，CHIBCHA）、日本人（1,000例和1,000例对照）和非洲裔美国人（1,500例和1,500例对照，R01CA126895, Le Marchand）进行风险估计的异质性分析。我们将在几个西班牙裔人群（注：由欧盟或美国国立卫生研究院资助的数据收集研究，而不是GWAS）的主要和联合分析中复制显著snp的基因型，包括：800名波多黎各人、2000名巴西人、2000名阿根廷人和3000名西班牙/葡萄牙人，以评估研究结果的通用性。该研究将通过解决与CRC遗传易感性相关的种族/民族差异的关键问题产生重大影响，并将通过提供遗传数据和生物标本资源来促进西班牙裔研究的进一步发展和投资，这是目前缺乏的。

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.