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Evidence for a genetical contribution to non-smoking-related lung cancer. BACKGROUND: The majority of lung cancers are smoking-related, with environmental and genetical factors contributing. The interplay between environmental and genetical contributions in non-smoking-related lung cancers is less clear. METHODS: We analysed a population-based computerised genealogy resource linked to a state-wide cancer registry of lung cancer cases (n=5544) for evidence of a genetical contribution to lung cancer predisposition in smoking (n=1747) and non-smoking cases (n=784). Statistical methods were used to test for significant excess relatedness of cases and estimate relative risk (RR) in close and distant relatives of lung cancer cases. RESULTS: Significant excess relatedness was observed for all lung cancer cases (p<0.001) and for the subsets of smoking-related (p<0.001) and non-smoking-related (p<0.001) cases when all pairwise relationships were considered. Only the non-smoking-related subset of cases showed significant excess relatedness when close relationships were ignored (p=0.020). First-degree, second-degree, and fourth-degree relatives of non-smoking-related lung cancer cases had significantly elevated RR. An even higher elevated RR was observed for first-degree, second-degree, third-degree and fourth-degree relatives of smoking-related lung cancer cases. CONCLUSIONS: Non-smoking-related lung cancer cases show significant excess relatedness for close and distant relationships, providing strong evidence for a genetical contribution as well as an environmental contribution. Significant excess relatedness for only close family relationships in all lung cancer cases and in only smoking-related lung cancer cases implies environmental contribution. Additionally, the highest RR for lung cancer was observed in the relatives of smoking-related lung cancer, suggesting predisposition gene carriers who smoke are at highest risk for lung cancer. Screening and gene identification should focus on high-risk pedigrees.