Lung cancer remains the leading cause of
cancer death in the United States and is one of the world's leading causes of preventable death. Technologic advances have brought new modalities that may be useful for the early detection of
lung cancer. However, because of the large number of persons at increased risk for
lung cancer, screening is a formidable task. There are several risk factors that can be identified, including potential susceptibility factors, which may aid in pinpointing individuals who need to participate in regular screening programs. Aside from recognized environmental exposures including cigarette smoking, there are a number of genetic and metabolic susceptibility factors that have been examined. These include polymorphisms in the
cytochrome p450 enzymes and the metabolizing capability of
glutathione s-transferase or acetylation. Additionally, defects in DNA repair and
in bleomycin sensitivity assays may also aid in identifying individuals who are at an increased risk for
lung cancer. Additional work has been done in the area of characterizing the molecular alterations in the bronchial epithelium in high-risk smokers. This manuscript addresses only selected molecular alterations that have been examined in preneoplastic bronchial epithelium. In addition to mutations in the k-ras oncogene and the p53 gene, which are frequently seen in
malignancy, alterations in the p16 gene,
microsatellite instability and loss of heterozygocity are also promising potential markers of preneoplasia. The
hnRNP A2/B1 gene also shows some promising increased expression in preneoplasia.
Lung cancer prevention has made some strides. A number of trials with molecular and morphologic intermediate endpoints have been conducted and have suggested that some of the molecular alterations and morphologic alterations are reversible. However, the rate of
spontaneous regression of these lesions is, as yet, uncharacterized. Two recent large studies, the
beta-carotene and
retinol efficacy trial (CARET) trial conducted in the United States and the
Alpha-Tocopherol Beta Carotene (ATBC) trial conducted in Finland, both demonstrated an unexpected increased risk for
lung cancer associated with
beta-carotene supplementation. The EUROSCAN trial evaluation of
vitamin A and
N-acetylcystine also showed no benefit to supplementation in reducing risk for
lung cancer. Results from the Intergroup study of 1 3-cis-retinoic
acid are pending, and plans are underway for an Intergroup trial studying high
selenium yeast to reduce
lung cancer risk. Hopefully, the combination of identifying markers of increased risk among the numerous current and former smokers will identify high-risk populations to participate in future trials of promising agents that may lead to reduction in incidence and mortality of the leading cause of
cancer death.