International Lung Cancer Consortium: Pooled Analysis of Genetic Determinants of

描述（由申请人提供）：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。肺癌的家族聚集性已被观察到，家族相对危险度为2倍，最近的连锁分析揭示了6q23-25可能的易感位点。然而，肺癌的确切遗传机制在很大程度上仍不清楚。在肺癌遗传学知识方面仍然存在主要的空白，包括：(1)肺癌阳性家族史的影响，特别是按组织学类型和从不吸烟者，以及(2)低外显率和中等外显率遗传变异的贡献。单一的研究不太可能有足够的力量为这些问题提供有力的答案，这突出了跨研究进行国际合作的必要性。国际肺癌联盟（ILCCO）是一个由肺癌研究人员组成的国际组织，成立于2004年，旨在分享正在进行的肺癌病例对照和队列研究的可比数据。总体目标是获得更大的权力，特别是对于子组分析，减少重复的研究工作，复制新的发现，并通过大规模的合作努力提供大量的成本节约。我们建议进行汇总分析来评估家族史对非吸烟者的影响，并进行协调基因分型来调查低至中等外显率遗传变异的贡献。我们的假设是：(1)阳性的肺癌家族史可能因组织学类型和吸烟状况而异；(2)常见的遗传变异影响肺癌风险，并可归因于至少部分肺癌病例。我们的具体目标是：(1)结合21项肺癌研究的数据，评估肺癌阳性家族史对总体肺癌发病风险的贡献，以及先证者的年龄、从不吸烟者和组织学亚型。我们还将（ii）对潜在的肺癌易感性变异进行协调的基因分型，这些变异由ILCCO成员提名，并根据证据的强度、生物学合理性和先前的独立重复进行选择。最后，我们将（iii）对基因分型数据进行汇总分析，以证实或反驳这些序列变异对整体肺癌的影响，以及对罕见的感兴趣亚组的影响，包括从不吸烟、发病年龄小、家族病例和组织学亚型。

DESCRIPTION (provided by applicant): 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. Familial aggregation has been observed in lung cancer with familial relative risk of 2-fold and a recent linkage analysis has revealed a possible susceptibility locus at 6q23-25. However, the exact inheritance mechanism of lung cancer is still largely undefined. Major gaps remain in knowledge of lung cancer genetics including (i) the effect of positive family history of lung cancer, particularly by histological type and among never smokers, and (ii) the contribution of low and moderate penetrance genetic variants. Single studies are unlikely to be sufficiently powered to provide robust answer to these questions highlighting the need for international collaboration across studies. The International Lung Cancer Consortium (ILCCO) is an international group of lung cancer researchers established in 2004 with the aim of sharing comparable data from ongoing lung cancer case-control and cohort studies. The overall objectives are to achieve greater power, especially for subgroup analyses, reduce duplication of research effort, replicate novel findings, and afford substantial cost savings through large collaborative efforts. We propose to conduct pooled analyses to evaluate the effect of family history among never smokers, and conduct coordinated genotyping to investigate the contribution of low to moderate penetrance genetic variants. Our hypotheses are (i) positive family history of lung cancer may differ by histological type and also by smoking status, and ii) common genetic variants influence lung cancer risk and attributable to at least part of the lung cancer cases. Our specific aims are (i) to combine data from 21 lung cancer studies to evaluate the contribution of positive family history of lung cancer to the risk of developing lung cancer overall, as well as by age of the proband, in never smokers and by histological subtype. We will also (ii) conduct coordinated genotyping on potential lung cancer susceptibility variants, which are nominated by ILCCO members and chosen based on the strength of the evidence, biological plausibility, and previous independent replications. Finally we will (iii) conduct pooled analysis of genotyping data, in order to confirm or refute the effect of these sequence variants on lung cancer overall, as well as in rare subgroups of interest including never smokers, young age of onset, familial cases and on histological subtypes.