ALLELE-SPECIFIC CHROMOSOME 3P DELETIONS OCCUR AT AN EARLY-STAGE IN THE PATHOGENESIS OF LUNG-CARCINOMA

Background.-Deletions in the short arm of chromosome 3 (3p) are presen t in most lung carcinomas. Objective.-To investigate the role of these chromosome 3p deletions in the pathogenesis of non-small cell lung ca rcinomas. Design.-Seven archival, paraffin-embedded, surgically resect ed lung cancer specimens were studied. Fifty precisely identified mali gnant and preneoplastic lesions present in bronchi, bronchioles, and a lveoli were microdissected from stained slides and analyzed for allele loss using polymerase chain reaction-based assays for dinucleotide re peat polymorphisms at three chromosome 3p loci (3p14, 3p21.3, and 3p25 ). Setting.-University-based medical center and affiliated hospitals. Subjects.-Samples were analyzed from seven patients who underwent surg ical resection with curative intent for non-small cell lung cancer and whose specimens included extensive multifocal areas of preneoplastic lesions (hyperplasia, metaplasia, dysplasia, or noninvasive cancer). R esults.-Lymphocytes from all seven cases were heterozygous (ie, inform ative) for all three microsatellites analyzed. Six (86%) of seven inva sive cancers had loss of heterozygosity at one or more chromosome 3p s ites. In the accompanying preneoplastic lesions, loss of heterozygosit y was detected in none of two normal bronchioles, 13 (76%) of 17 hyper plasias, six (86%) of seven dysplasias, and four (100%) of four noninv asive cancers. Loss of heterozygosity was detected throughout the resp iratory tract, in bronchi, bronchioles, and alveoli. In 18 (78%) of 23 preneoplastic lesions, the specific alleles lost were identical to th ose lost in the corresponding carcinomas. The probability of this happ ening by chance is 5.3x10(-3). Conclusions.-Deletions in the short arm of chromosome 3 occur at the earliest stage (hyperplasia) in the path ogenesis of lung cancer and involve all regions of the respiratory tra ct. Allele loss is highly specific, but its mechanism remains unknown. Our findings may be of considerable biologic, prognostic, and clinica l significance.