GENETICS OF TOBACCO AND ALCOHOL RELATED CANCERS

描述（由申请人提供）：在最初的补助金（R 01 CA 092039- 01 A2）的前30个月，我们通过鉴定与肺癌和上呼吸消化道（UADT）癌症密切相关的几个基因，包括CHEK 2和ADH 1B，成功地促进了我们对肺癌和UADT癌症遗传流行病学的理解。我们还证明了遗传变异如何与这些癌症的饮食和环境暴露强烈相互作用。鉴于过去3年中遗传信息的巨大增加，我们计划在初步结果的基础上，全面评估基因在这些癌症的5个特定途径中的作用。为了检验所观察到的正相关性的稳健性，我们将在其他大型研究中进行独立复制。因此，我们提出了一个多阶段的研究，具有以下具体目标：第1阶段将涉及2200个欧洲肺癌病例对照对和1000个UADT癌症病例对照对中的5个候选基因通路的综合评价，涉及超过1500个信息变异以及生物学相关变异的纳入。第2阶段将涉及快速复制其他大型独立欧洲研究中的重要阳性结果，包括（i）基于1200例肺癌病例和2400例对照的EPIC肺癌，以及（ii）2000例UADT癌症病例-对照对的“ARCAGE”西欧研究。从第1阶段到第2阶段的变体选择将基于结合基因组信息（如序列保守性）的分层贝叶斯方法。重要的已确认基因将在拉丁美洲UADT癌症的第三项IARC研究中重新测序并进一步复制，该研究包括2000对头颈癌病例对照对。作为该提案的一个重要组成部分，我们将对复制的基因进行功能研究，包括差异mRNA表达。所有结果将通过肺癌和头颈癌两个国际联盟的合作提供给烟草和酒精相关癌症的研究界。研究与公共卫生的相关性：大型遗传流行病学研究有可能确定患癌症风险特别高的个体，并帮助确定这些癌症发生的原因。通过整合与烟草和酒精相关的癌症（特别是肺癌和UADT癌症）的多项大型研究，我们的目标是提供知识，为未来的预防工作提供信息。

DESCRIPTION (provided by applicant): During the first 30 months of the original grant (R01 CA 092039-01A2), we have successfully contributed to our understanding of the genetic epidemiology of lung cancer and upper aerodigestive tract (UADT) cancer by identification of several genes that are very strongly associated with them, including CHEK2 and ADH1B. We have also demonstrated how genetic variants interact strongly with dietary and environmental exposures for these cancers. Given the enormous increase in genetic information over the last 3 years we plan to build on our initial results and comprehensively evaluate the role of genes in 5 specific pathways for these cancers. To test the robustness of the positive associations observed, we will conduct independent replication of findings in other large studies. We therefore propose a multistage study with the following specific aims: Stage 1 will involve a comprehensive evaluation of 5 candidate gene pathways among 2200 European case-control pairs of lung cancer and 1000 case-control pairs of UADT cancer, involving over 1500 informative variants as well as inclusion of biologically relevant variants. Stage 2 will involve rapid replication of important positive results in other large independent European studies including (i) EPIC lung cancer based on 1200 lung cancer cases and 2400 controls, and (ii) the 'ARCAGE' Western European study of 2000 case-control pairs of UADT cancer. The choice of variants passing from Stage 1 to Stage 2 will be based on hierarchical bayes approach incorporating genomic information such as sequence conservation. Important confirmed genes will be resequenced and further replicated in a third IARC study of UADT cancer from Latin American study comprising 2000 case-control pairs of head and neck cancer. As an important component of this proposal, we will conduct functional studies of the genes that are replicated including differential mRNA expression. All results will be made available to the research community of tobacco and alcohol related cancers via collaboration within 2 international consortia of lung cancer and head and neck cancers. Relevance of research to public health: Large genetic epidemiology studies have the potential to identify individuals at particularly high risk of developing cancer, as well as helping identify why these cancers develop. By incorporating multiple large studies of cancers related to tobacco and alcohol (specifically lung, and UADT cancer) we aim to provide knowledge that will inform future prevention efforts.