Pooled Analyses of SNPs and Risk of Head & Neck Cancer

SNP 和头部风险的汇总分析

• 批准号: 6904958
• 负责人: MIA HASHIBE
• 金额: $ 11.3万
• 依托单位: INTERNATIONAL AGENCY FOR RES ON CANCER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6904958
• 关键词: DNA repair; NAD(P)H dehydrogenase; biotechnology; cancer risk; carcinogenesis; cooperative study; cytochrome P450; epoxide hydrolase; gene environment interaction; gene expression; gene interaction; genetic markers; genetic screening; glutathione transferase; head /neck neoplasm; human tissue; miscellaneous oxidoreductase; neoplasm /cancer diagnosis; neoplasm /cancer genetics; oncogenes; phosphoester ligase; single nucleotide polymorphism; statistics /biometry

DESCRIPTION (provided by applicant): Previous molecular epidemiology studies on head and neck cancer have examined one to several single nucleotide polymorphisms (SNPs) among several hundred cases and controls, focusing on sequence variants in carcinogen metabolism and DNA repair genes. The inconsistent results observed across these studies may be due to: i) low statistical power in detecting modest risk sequence variants, ii) false positive results, iii) publication bias, and iv) a moderate prior probability that each SNP individually confers substantial increase in risk. Furthermore, examining the main effects of one or few modest risk sequence variants is an overly simplified approach, when considering that carcinogenesis is highly complex, with numerous genes acting on multiple pathways plus their interactions with environmental factors. Moving from single marker analyses to tests of multiple SNPs and gene-environment interactions is necessary, but requires considerable sample size and statistical power. Therefore, we propose to conduct pooled analyses within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, a recently established collaboration of research groups leading large molecular epidemiology studies of head and neck cancer. We will combine data from 7 US studies and 3 European studies on more than 5000 case-control pairs for 18 SNPs. Our specific aims are: 1) to conduct pooled analysis on 11 SNPs in genes that encode carcinogen metabolizing enzymes and the risk of head and neck cancer, 2) to conduct pooled analysis on 7 SNPs in DNA repair genes, 3) to apply novel statistical methods including the assessment of false positive report probability and hierarchical modeling approaches to address the possibility of false positive results and to incorporate prior knowledge on these genes. The hypotheses of interest are: a) SNPs in the carcinogen metabolism and DNA repair genes confer an increased risk of head and neck cancer, and the magnitude of effect of each SNP is modest b) inheritance of multiple alleles at these loci confer a higher risk of head and neck cancer, c) there are multiple gene-gene and gene-environment interactions among these sequence variants and environmental factors. We believe that our proposed analyses is a cost effective approach in generating data for a large head and neck cancer study, that will address the limitation of previous studies and provide a clearer picture of the role of these SNPs in head and neck cancer carcinogenesis.

描述（由申请人提供）：之前对头颈癌的分子流行病学研究已经检查了数百个病例和对照中的一到几个单核苷酸多态性（SNP），重点关注致癌物代谢和DNA修复基因中的序列变异。这些研究中观察到的不一致结果可能是由于：i) 检测中等风险序列变异的统计功效较低，ii) 假阳性结果，iii) 发表偏倚，以及 iv) 每个 SNP 单独导致风险大幅增加的中等先验概率。 此外，考虑到致癌过程非常复杂，众多基因作用于多种途径，再加上它们与环境因素的相互作用，检查一个或几个中等风险序列变异的主要影响是一种过于简化的方法。从单一标记分析转向多个 SNP 和基因-环境相互作用的测试是必要的，但需要相当大的样本量和统计能力。因此，我们建议在国际头颈癌流行病学 (INHANCE) 联盟内进行汇总分析，该联盟是最近成立的由领导头颈癌大分子流行病学研究的研究小组组成的合作组织。我们将结合 7 项美国研究和 3 项欧洲研究的数据，涉及 18 个 SNP 的 5000 多个病例对照对。我们的具体目标是：1) 对编码致癌物代谢酶和头颈癌风险的基因中的 11 个 SNP 进行汇总分析，2) 对 DNA 修复基因中的 7 个 SNP 进行汇总分析，3) 应用新的统计方法，包括评估假阳性报告概率和分层建模方法，以解决假阳性结果的可能性，并纳入有关这些基因的先验知识。感兴趣的假设是：a) 致癌物代谢和 DNA 修复基因中的 S​​NP 会增加患头颈癌的风险，并且 每个 SNP 的影响是适度的 b) 这些位点的多个等位基因的遗传会导致头颈癌的较高风险，c) 这些序列变异和环境因素之间存在多种基因-基因和基因-环境相互作用。我们相信，我们提出的分析是为大型头颈癌研究生成数据的一种具有成本效益的方法，它将解决先前研究的局限性，并更清楚地了解这些 SNP 在头颈癌致癌过程中的作用。