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）：对头颈癌的先前分子流行病学研究检查了几百例和对照中的一到几个单核苷酸多态性（SNP），重点是致癌代谢和DNA修复基因的序列变体。在这些研究中观察到的不一致的结果可能是由于：i）较低的统计能力检测适度的风险序列变体，ii）假阳性结果，iii）出版偏见，iv）每个SNP单独构成大量风险大幅增加的中等先前概率。 此外，研究一种或几个适度的风险序列变体的主要影响是一种过度简化的方法，当考虑到致癌作用非常复杂时，许多基因在多个途径上起作用，加上与环境因素的相互作用。从单个标记分析转变为多个SNP和基因环境相互作用的测试，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）联盟中进行汇总分析，这是最近建立的研究小组的合作，领导了头颈癌大型分子流行病学研究。我们将结合来自美国7项研究的数据和3项关于5000多个病例对照对的研究，用于18个SNP。我们的具体目的是：1）在编码致癌代谢酶的基因和头颈癌的风险的基因中进行汇总分析，2）在DNA修复基因中对7个SNP进行汇总分析，3）应用新颖的统计方法，包括虚假的阳性报告的概率和层次模型方法的评估，以解决虚假的依从物质，以解决误差的结果，并结合了这些物质，并结合了这些物质的结果，并结合了这些统计方法。感兴趣的假设是：a）致癌代谢中的SNP和DNA修复基因赋予头颈癌的风险增加，以及的大小 每个SNP的效果是适度的b）在这些基因座的多个等位基因的遗传赋予头颈癌的较高风险，c）这些序列变体和环境因素之间存在多种基因基因和基因 - 环境相互作用。我们认为，我们提出的分析是为大型头颈癌研究生成数据的一种经济有效方法，该方法将解决以前的研究的局限性，并更清楚地了解了这些SNP在头和颈癌中的作用。