GENETICS OF TOBACCO AND ALCOHOL RELATED CANCERS

描述（由申请人提供）：在原始资助（R01 CA 092039-01A2）的前30个月，我们通过鉴定几个与肺癌和上气消化道（UADT）癌症密切相关的基因，包括CHEK2和ADH1B，成功地对肺癌和上气消化道（UADT）癌症的遗传流行病学做出了贡献。我们还证明了遗传变异如何与饮食和环境暴露密切相互作用，从而导致这些癌症。鉴于过去三年遗传信息的巨大增长，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种特定途径中的作用。为了检验所观察到的正相关性的稳健性，我们将对其他大型研究中的发现进行独立的复制。因此，我们提出了一项多阶段研究，其具体目标如下：第一阶段将包括对2200对欧洲病例对照肺癌和1000对UADT癌症病例对照中的5个候选基因通路进行全面评估，涉及超过1500个信息性变异以及包括生物学相关的变异。第二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) EPIC肺癌研究，该研究基于1200例肺癌病例和2400例对照，以及（ii）西欧“ARCAGE”研究，该研究包含2000对UADT癌症病例对照。从阶段1过渡到阶段2的变异选择将基于层次贝叶斯方法，结合序列保守等基因组信息。重要的已确认基因将在国际癌症研究机构第三项来自拉丁美洲的UADT癌症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。作为该提案的一个重要组成部分，我们将对被复制的基因进行功能研究，包括mRNA的差异表达。所有结果将通过两个国际肺癌和头颈癌协会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，并有助于确定这些癌症发生的原因。通过整合多项与烟草和酒精相关的癌症（特别是肺癌和UADT癌症）的大型研究，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.