GENETICS OF TOBACCO AND ALCOHOL RELATED CANCERS

描述(申请人提供)：在最初拨款的前30个月(R01 CA 092039-01A2)，我们通过识别几个与肺癌和上呼吸道癌症密切相关的基因，成功地促进了我们对肺癌和上呼吸道癌症的遗传流行病学的了解，包括CHEK2和ADH1B。我们还展示了基因变异如何与这些癌症的饮食和环境暴露强烈相互作用。鉴于基因信息在过去三年中的巨大增长，我们计划在我们初步结果的基础上，全面评估基因在这些癌症的5条特定途径中的作用。为了测试所观察到的积极关联的稳健性，我们将独立复制其他大型研究的结果。因此，我们提出了一项多阶段研究，具体目标如下：第一阶段将对2200对欧洲肺癌病例对照和1000对UADT癌症病例对照中的5条候选基因通路进行全面评估，涉及1500多个信息性变异，以及纳入生物学相关的变异。第二阶段将涉及快速复制其他大型独立欧洲研究的重要积极结果，包括(I)基于1200例肺癌病例和2400名对照的史诗肺癌研究，以及(Ii)对2000对UADT癌症病例-对照的“ARCAGE”西欧研究。从阶段1到阶段2的变异体的选择将基于融合了基因组信息的分层贝叶斯方法，例如序列保守。重要的已确认基因将被重新测序，并在IARC对拉丁美洲UADT癌症的第三项研究中进一步复制，该研究包括2000对头颈部癌症病例对照。作为这一提议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。所有结果都将通过两个国际肺癌和头颈癌联合会的合作提供给与烟草和酒精有关的癌症研究界。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罹患癌症风险特别高的个人，并有助于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.