We will conduct an interdisciplinary case-control/sib-pair study of lung cancer designed to explore the genetic determinants both of lung cancer and of smoking. The study includes biospecimen collection as well as exposure information with power to address main genetic effects and gene-environment interactions.

This is an integrated proposal designed to address two major issues: the genetic determinants of lung cancer in smokers and the genetic determinants of smoking. Other important issues will be addressed in the study with a marginal additional cost to the main design. The study achieves excellent power for studying the main effects of genetic factors that are relatively common and good power for formal tests of interactive effects.

Using a case-control design, with questionnaire, medical record abstraction, and blood collection, we will investigate: main effects of genes on lung cancer risk; gene-environment and gene-gene effects in lung cancer etiology; gene effects on smoking persistence; gene effects on ever-never smoking; gene-psychological interactions in smoking behaviors.

In addition, we will collect viable lymphocytes from all study subjects and tumor, metaplastic and normal tissue samples from 100 surgical cases. With these data and tissues, we will be able to study: genetic instabilities in lung cancer tissue in relation to specific exposures, genotype, persistence of smoking, and clinical presentation of lung cancer; histologic characteristics of lung cancer in relation to genotype, gene expression, somatic mutations, and smoking; functional assays in viable lmphocytes in relation to genotype, gene expression.

Finally, we will identify lung cancer-affected siblings of cases, and the unaffected siblings in the same sibships. This sample will permit us to: replicate associations found in the case-control sample with an alternative analytical method based on transmission statistics; address some population stratification issues.

• INCLUSION CRITERIA - CASE GROUP:

The case group will consist of 2,000 newly incident lung cancer cases, male and female, 35 to 79 years old, with verified lung cancer, collected before or after surgery and prior to chemotherapy or radiation therapy.

All histologic types and all stages of lung cancer will be eligible.

Cases will be consecutively collected in the departments of thoracic surgery, general surgery, general medicine, and oncology.

The pool of cases will be residents of Lombardy derived from 5 cities (Milan, Brescia, Varese, Monza, and Pavia) and the surrounding residential villages served by 14 hospitals, that encompass all five medical schools in the region.

Enrolled cases will have no history of other cancers, except for basal cell carcinoma of the skin or in situ cervical carcinoma.

Subjects in intensive care units, or with cardiac, hepatic, renal, or CNS failure, or with uncompensated schizophrenia, psychosis, or inability to speak, will not be enrolled.

All subjects will sign an informed consent.

INCLUSION CRITERIA - CONTROL GROUP:

The control group will consist of 2,000 gender-, age-, and county-matched controls with no history of cancer.

We will choose a population-based or hospital-based control group depending on the result of a pilot study.