Whole Genome Scan for Modifier Genes in Colorectal Cancer

全基因组扫描结直肠癌修饰基因

• 批准号: 7926367
• 负责人: LOIC LE MARCHAND
• 金额: $ 180.27万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926367
• 关键词: Admixture; Adopted; African American; Alcohols; Biological; Blood specimen; Calcium; Cancer Center; Characteristics; Clinical Data; Cohort Studies; Collaborations; Colon; Colorectal Cancer; Communities; Confidentiality; Consumption; CpG Island Methylator Phenotype; DNA; Data; Data Set; Defect; Development; Diagnostic; Disease; Environment; Environmental Risk Factor; Ethnic group; Folate; Funding; Gene-Modified; Genes; Genetic; Genetic Variation; Genome; Genome Scan; Genomics; Genotype; Genus Cola; Hand; Haplotypes; Hawaii; Hawaiian population; Heterogeneity; Incidence; Individual; Inherited; Institutes; Investments; Japan; Japanese American; Japanese Population; Large Intestine; Latino; Life Style; Link; Linkage Disequilibrium; Los Angeles; Malignant Neoplasms; Meat; Methods; Microsatellite Instability; Mismatch Repair; Modeling; Morbidity - disease rate; Mutation; Online Systems; Overnutrition; Participant; Pathway interactions; Play; Policies; Population; Population Genetics; Predisposition; Prevention; Primary Prevention; Public Health; Rectal Cancer; Relative (related person); Research; Research Personnel; Resources; Risk; Risk Assessment; Risk Factors; Role; Sampling; Screening procedure; Secure; Single Nucleotide Polymorphism; Smoking; Staging; Stratification; Surveys; Susceptibility Gene; Syndrome; Technology; Testing; Therapeutic; Tokyo; United States National Institutes of Health; Variant; Vitamin D; analytical method; base; beef; biobank; calcium intake; cancer genetics; cancer risk; cohort; data sharing; design; experience; gene environment interaction; genetic variant; genome wide association study; genome-wide; high risk; molecular phenotype; mortality; novel; novel therapeutic intervention; population based; public health relevance; racial and ethnic; racial/ethnic difference; sample collection; statistics; tumor

DESCRIPTION (provided by applicant): Common inherited DNA variants are expected to play an important role in colorectal cancer (CRC). However, the main effects for these variants are likely to be weak because as much as 75-80% of CRC cases are "explainable" by known or suspected lifestyle risk factors. Most importantly, recent evidence suggests that common genetic factors for CRC act by amplifying these environmental effects. It is now practical to comprehensively study association with inherited DNA variation genome-wide. We propose to build on existing collaborations to undertake such a study using a multiethnic cohort representing the diversity of the U.S. population and a Japanese cohort. We have established a large biorepository linked to detailed, pre-diagnostic lifestyle exposure information and clinical data for five racial-ethnic groups in the Multiethnic Cohort study (MEC), as well as for Japanese in Japan in the Japan Public Health Center cohort study (JPHC). We will perform a two-stage, well powered, population-based, genome-wide association study of CRC in the MEC and JPHC, concentrating on both main effects and gene-environment interactions. In Stage 1, we will test ~1 million single nucleotide polymorphisms (SNPs) for association with CRC in 1,000 cases and 1,000 controls of Japanese ancestry from the MEC and evaluate both the main effects of each SNP (overall and for colon and rectal cancers) and their interactions with a well-defined set of lifestyle variables (folate, red meat, alcohol and calcium intakes, and BMI and pack-years). About 16,000 of the most strongly associated variants (singly, by anatomical subsite, or interacting with these lifestyle risk factors) with risk will be further evaluated in Stage 2, using additional subjects, consisting of 3,000 CRC cases and 3,000 controls from the MEC (African Americans, Japanese Americans, Latinos, Native Hawaiians and Whites) and JPHC (Japanese). Significance and heterogeneity of effects will be assessed using a combined analysis of Stages 1 and 2. Data from this study will quickly be made available to the research community. The elucidation of modifying genes for CRC will identify new mechanistic pathways and generate a better biological understanding on which to base individual risk assessment and new therapeutic approaches. PUBLIC HEALTH RELEVANCE: This multiethnic study will interrogate the entire genome for association with inherited genetic variants that may increase risk of colorectal cancer, either independently or by amplifying the effects of specific lifestyle risk factors. The study will generate a better biological understanding of the disease on which to base new prevention and therapeutic approaches.

描述（由申请人提供）：预计常见的遗传DNA变异将在结直肠癌（CRC）中起重要作用。但是，这些变体的主要影响可能很弱，因为已知或怀疑的生活方式危险因素中，多达75-80％的CRC病例是“可解释”的。最重要的是，最近的证据表明，CRC的常见遗传因素通过扩大这些环境影响来起作用。现在，与遗传性DNA变异基因组的遗传性研究相关性现在是实际的。我们建议以现有的合作为基础，使用代表美国人口多样性和日本队列的多种族队列进行此类研究。我们已经建立了一个与五个种族族裔群体的详细，诊断前的生活方式暴露信息和临床数据相关的大型生物座席，在多民族队列研究（MEC）以及日本的日本公共卫生中心人群研究（JPHC）的日本日本。我们将对MEC和JPHC中的CRC进行两阶段，动力良好的基于​​人群的基因组关联研究，并集中于主要效应和基因环境相互作用。在第1阶段，我们将测试约100万个单核苷酸多态性（SNP）与MEC中的1000例CRC和1000个日本血统的对照相关，并评估每个SNP的主要影响（总体，结肠和直肠癌的总体以及它们的相互作用），以及它们与精确的生活时代的融合，redeys contely and Colles，redectal and Bullia和Bulme and Callim and Callim and Callim and Callim and Callim and Callim and Callim and Callim and Callim and Callim and Callim and Callim and Callim and Calcect。在第2阶段，将进一步评估大约16,000个最相关的变体（单独通过解剖学子站点或与这些生活方式风险因素互动）与风险进行进一步评估，使用其他主题，包括3,000例CRC案件和3,000例MEC（非洲裔美国人，日本美国人，拉美裔，夏威夷人和夏威夷人和WHITES和JPHC）和JPHC（日本）。效果的显着性和异质性将通过对第1和2阶段的联合分析进行评估。该研究的数据将迅速提供给研究界。阐明CRC的修饰基因将确定新的机械途径，并在基于个人风险评估和新的治疗方法上产生更好的生物学理解。公共卫生相关性：这项多种族研究将询问与遗传遗传变异的整个基因组，这些遗传变异可能会独立或通过扩大特定生活方式危险因素的影响来增加结直肠癌的风险。该研究将对以新的预防和治疗方法为基础的疾病产生更好的生物学理解。