Pooled Analyses of SNPs and Risk of Head & Neck Cancer

SNP 和头部风险的汇总分析

• 批准号: 7068606
• 负责人: MIA HASHIBE
• 金额: $ 11.03万
• 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/7068606
• 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）：以前的头颈癌分子流行病学研究已经在数百例病例和对照中检查了一种至几种单核苷酸多态性（SNP），重点是致癌物代谢和DNA修复基因的序列变异。在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体的统计功效低，ii）假阳性结果，iii）发表偏倚，以及iv）每个SNP单独赋予风险显著增加的中等先验概率。 此外，当考虑到致癌作用是高度复杂的，许多基因作用于多个途径以及它们与环境因素的相互作用时，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一个研究小组合作，领导头颈癌的大型分子流行病学研究。我们将结合来自7项美国研究和3项欧洲研究的联合收割机数据，对18个SNP的5000多个病例对照对进行研究。我们的具体目标是：1）对编码致癌物代谢酶的基因中的11个SNP与头颈癌风险进行汇总分析，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，并结合这些基因的先验知识。感兴趣的假设是：a）致癌物质代谢和DNA修复基因中的SNP赋予头颈癌的增加的风险，并且 每个SNP影响是适度的，B）在这些基因座上的多个等位基因的遗传赋予头颈癌的更高风险，c）在这些序列变体和环境因素之间存在多个基因-基因和基因-环境相互作用。我们认为，我们提出的分析是一种成本效益高的方法，可以为大型头颈癌研究提供数据，这将解决以往研究的局限性，并更清楚地了解这些SNP在头颈癌致癌作用中的作用。