Familial aggregation of lung cancer was first reported over 30 years ago. A recent genetic epidemiology study found that the pattern of lung cancer occurrance in families was consistent with Mendelian codominant inheritance of a rare autosomal gene with variable age at onset. In addition, evidence from genetic studies suggests that genetically- determined polymorphisms in the microsomal mixed-function oxidases (cytochrome P450s) affect risk of lung cancer. Tumor suppressor genes also have been identified which appear to play a role in familial cancers. Our goal is to evaluate the role of genes and the environment in the etiology of lung cancer, focusing on two risk groups expected to have risk associated with genetic susceptibility. These groups include non-smokers and persons under age 45 years at diagnosis. This population-based case-control study will include approximately 250 non- smoking lung cancer cases age 40-84 years, 250 non-smoking, non-cancer controls age 40-84 years, 400 lung cancer cases under 45 years of age selected without regard to smoking status and 400 non-cancer controls under 45 years of age. The cases are identified through the Metropolitan Detroit Cancer Surveillance System, a participant in NCI's SEER program. These cases and controls, or their proxies, will provide detailed questionnaire data, through a telephone interview, about environmental exposures for their parents, siblings, children and spouse (approximately 10,000 individuals in total). Tumor specimens for cases will be obtained, as will blood samples from controls, for genetic analyses. This study population, which is 29% black and 59% female, will be used to address the following specific aims: 1) to determine if there is heterogeneity of lung cancer risk among families after accounting for individually measured environmental risk factors; 2) to determine if the contribution to risk from familial factors and individual exposures varies by histologic type and race; 3) to determine if there is familial heterogeneity for risk of other cancers and other respiratory diseases; 4) to determine the contribution of genetic and environmental factors to the distribution of lung cancer, other cancers, and other respiratory diseases in families; 5) to evaluate differences in risk of lung cancer by genotype at the P450 loci, CYP1A1 and CYP2E1, in cases and controls; 6) to determine the frequency and type of mutations at the p53 tumor suppressor locus in the cases; and 7) to determine if a correlation exists between the frequency and nature of identified p53 mutations and P450 genotypes. The proposed project represents a logical progression in defining the contribution of genes and environment in risk of lung cancer. The interview component will provide us with data about individually measured environment risk factors which need to be accounted for when determining familial risk. Familial risk will be resolved into its components using segregation analysis to determine contributions from unmeasured, shared environments and from genetic inheritance. We look for specific genes that may be responsible for increased susceptibility and describe genetic changes at the tumor level. This is a powerful strategy, made even more powerful by the unique study populations and the large sample size.
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