International Lung Cancer Consortium: Pooled analysis o*

描述（由申请人提供）： 肺癌仍然是最常见的癌症，也是全球癌症死亡的主要原因之一。虽然很明显，肺癌主要是由接触烟草制品引起的，但只有少数重度吸烟者会患上这种疾病。与癌症发展相关的个体间差异的主要来源可能是DNA修复能力。DNA修复基因的遗传变异被认为是调节DNA修复能力（DRC）的因素，因此被认为与癌症风险有关。然而，流行病学研究的结果并不一致。这可能是由于（i）检测中度效应的统计功效较低，（ii）假阳性结果，（iii）未考虑效应修饰因子，如环境暴露，以及（iv）出版偏倚。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，检查单个中等风险序列变异的主要影响是一种过于简化的方法。 从单标记分析到多基因效应和基因-环境相互作用的研究是必要的，但需要相当大的样本量和统计能力。因此，我们建议在国际肺癌联盟（ILCCO）内进行汇总分析，ILCCO是一个最近成立的国际肺癌研究人员组织，目的是共享来自正在进行的肺癌病例对照和队列研究的可比数据。我们将结合来自11项研究的联合收割机数据，其中4项来自美国，6项来自欧洲，1项来自亚洲，导致超过10，000例病例和12，000例对照，以评估11个DNA修复基因中19个SNP的作用。研究假设为：（i）DNA修复基因的序列变异可适度增加肺癌风险，（ii）多种先前风险基因型的组合可增加风险，（iii）遗传关联因环境暴露的存在而改变。我们的具体目标是：1）通过途径研究11个DNA修复基因中19个遗传多态性的独立和联合作用，2）评估环境致癌物（如吸烟）的效应修饰，并评估SNP单独或组合对特别感兴趣的亚组（包括年轻发病年龄，罕见组织学，家族性病例）癌症风险的贡献，3）进行相关的统计分析，包括分层模型和假阳性报告概率（FPRP）的计算，以解决多重比较的问题; 4）通过建立一个网站来公布联盟的资源，以提高联合研究的效率。我们相信，我们提出的分析是一种成本效益高的方法，可以为大型肺癌研究提供数据，这将解决以往研究的局限性，并证实这些SNP在肺癌发生中的作用。

DESCRIPTION (provided by applicant): Lung cancer continues to be the most common cancer overall and one of the leading causes of cancer death worldwide. While it is apparent that lung cancer is predominantly caused by exposure to tobacco products, only a minority of heavy smokers will develop this disease. A major source of inter-individual variability in relation to the development of cancer is likely to be DNA repair capacity. Genetic variations of DNA repair genes are thought to moderate DNA Repair Capacity (DRC), and consequently are suggested to be related to cancer risk. However, the results from epidemiological studies have been inconsistent. This is likely to be due to (i) low statistical power for detecting a moderate effect, (ii) false positive results, (iii) failure to consider effect modifiers such as environmental exposures, and (iv) publication bias. Furthermore, examining the main effects of single 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 investigation of multigenic effect and gene-environment interactions is necessary, but requires considerable sample size and statistical power. Therefore, we propose to conduct pooled analyses within the International Lung Cancer Consortium (ILCCO), a recently established international group of lung cancer researchers with the aim of sharing comparable data from ongoing lung cancer case-control and cohort studies. We will combine data from 11 studies, including 4 from US, 6 from Europe and 1 from Asia, resulting in over 10,000 cases and 12,000 controls, to evaluate the role of 19 SNPs in 11 DNA repair genes. The study hypotheses are that: (i) sequence variants in DNA repair genes confer modestly increased risks of lung cancer, (ii) a combination of multiple prior risk-genotypes confers a higher risk and (iii) genetic associations are modified by the presence of environmental exposures. Our specific aims are 1) to investigate the independent and joint effects of 19 genetic polymorphisms in 11 DNA repair genes by pathway, 2) to assess effect modification of environmental carcinogens such as tobacco smoking, and to evaluate the contribution of SNPs, individually or in combination, to cancer risk in subgroups of particular interests, including young age of onset, rare histologies, familial cases, and never smokers, 3) to conduct relevant statistical analyses including hierarchical modeling and calculation of false positive report probabilities (FPRP), in order to address the problem of multiple comparisons, 4) to increase the efficiency of joint research by establishing a website that will publicize the resources of the consortium. We believe that our proposed analyses is a cost effective approach in generating data for a large lung cancer study, that will address the limitation of previous studies and confirm the role of these SNPs in lung carcinogenesis.