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.
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