Patterns of allelic loss differ in lung adenocarcinomas of smokers and nonsmokers

Cigarette smoking is the most important cause of lung cancer, however approximately 10% of patients with lung cancer have no history of smoking. While the molecular pathogenesis of smoking associated lung carcinogenesis is becoming well characterized, the pathogenesis of lung cancer in nonsmokers is not. We designed a study to examine the pathogenesis of adenocarcinoma in nonsmokers by determining if loss of heterozygosity (LOH) in tumors of nonsmokers differs from those of smokers. We evaluated six cases of primary adenocarcinoma in never smokers and six selected cases in smokers, matched by clinical and histological criteria. LOH in tumor DNA relative to nonmalignant lung DNA was determined at 52 microsatellites located on ten chromosomal loci. The extent of allelic loss in smokers, as measured by fractional allelic loss (FAL), was compared with nonsmokers. LOH was more frequent in the tumors of nonsmokers than of smokers with mean FAL of 46% in nonsmokers and 28% in smokers (P<0.05). Increased LOH in nonsmokers was most pronounced at chromosomes: 3p, 8p, 9p, 10p, and 18q. Since this study compared allelic loss between lung and tumor-bearing lung, less frequent LOH in smokers' tumors can be interpreted to suggest LOH was already present in the nonmalignant lung of smokers and fewer additional instances of allelic loss were present in the tumors of smokers. Our results suggest that the early steps of lung carcinogenesis differ in nonsmokers compared with smokers. In addition, the chromosomal sites of LOH may identify genes important for lung carcinogenesis in nonsmokers.