International Lung Cancer Consortium: Pooled Analysis of Genetic Determinants of

描述(申请人提供)：虽然很明显，肺癌主要是由接触烟草产品引起的，但只有少数重度吸烟者会患上这种疾病。在肺癌中观察到家族聚集性，家族性相对风险为2倍，最近的连锁分析揭示了6q23-25可能的易感基因。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差距，包括(I)肺癌阳性家族史的影响，特别是按组织类型和从不吸烟者的影响，以及(Ii)低和中等外显性基因变异的贡献。单一的研究不太可能有足够的力量对这些问题提供强有力的答案，这些问题突显了跨研究的国际合作的必要性。国际肺癌联合会(ILCCO)是一个由肺癌研究人员组成的国际组织，成立于2004年，目的是分享正在进行的肺癌病例对照和队列研究的可比数据。总体目标是实现更大的能力，特别是在子组分析方面，减少研究工作的重复，复制新的发现，并通过大规模的合作努力节省大量成本。我们建议进行合并分析，以评估家族史对从不吸烟者的影响，并进行协调基因分型，以调查低至中等外显性遗传变异的贡献。我们的假设是(I)肺癌阳性家族史可能因组织类型和吸烟状况而不同，以及ii)常见的基因变异会影响肺癌的风险，并可归因于至少部分肺癌病例。我们的具体目标是(I)结合21项肺癌研究的数据，评估肺癌阳性家族史对肺癌总体风险的贡献，以及先证者的年龄、从不吸烟者和组织亚型的贡献。我们还将(Ii)对潜在的肺癌易感变种进行协调基因分型，这些变种由ILCCO成员提名，并根据证据的强度、生物学上的可信程度和以前的独立复制来选择。最后，我们将(Iii)对基因分型数据进行混合分析，以确认或否定这些序列变异对肺癌的整体影响，以及对包括从不吸烟、发病年龄较小、家族性病例和组织学亚型在内的罕见感兴趣亚群的影响。

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.