Allele-Specific Chromosome 3p Deletions Occur at an Early Stage in the Pathogenesis of Lung Carcinoma

Abstract

BACKGROUND: Deletions in the short arm of chromosome 3 (3p) are present in most lung carcinomas. OBJECTIVE: To investigate the role of these chromosome 3p deletions in the pathogenesis of non-small cell lung carcinomas. DESIGN: Seven archival, paraffin-embedded, surgically resected lung cancer specimens were studied. Fifty precisely identified malignant and preneoplastic lesions present in bronchi, bronchioles, and alveoli were microdissected from stained slides and analyzed for allele loss using polymerase chain reaction-based assays for dinucleotide repeat 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 surgical 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). RESULTS: Lymphocytes from all seven cases were heterozygous (ie, informative) for all three microsatellites analyzed. Six (86%) of seven invasive cancers had loss of heterozygosity at one or more chromosome 3p sites. In the accompanying preneoplastic lesions, loss of heterozygosity was detected in none of two normal bronchioles, 13 (76%) of 17 hyperplasias, six (86%) of seven dysplasias, and four (100%) of four noninvasive cancers. Loss of heterozygosity was detected throughout the respiratory tract, in bronchi, bronchioles, and alveoli. In 18 (78%) of 23 preneoplastic lesions, the specific alleles lost were identical to those lost in the corresponding carcinomas. The probability of this happening by chance is 5.3 x 10(-3). CONCLUSIONS: Deletions in the short arm of chromosome 3 occur at the earliest stage (hyperplasia) in the pathogenesis of lung cancer and involve all regions of the respiratory tract. Allele loss is highly specific, but its mechanism remains unknown. Our findings may be of considerable biologic, prognostic, and clinical significance.