Molecular changes in the bronchial epithelium of patients with small cell lung cancer

To better understand the pathways involved in the pathogenesis of small cel l lung carcinoma (SCLC), we compared the patterns of molecular changes pres ent in these tumors and their accompanying bronchial epithelium with those present in the other two major types of lung cancer [squamous cell carcinom a (SQC) and adenocarcinoma (ADC)I, We obtained DNA from 68 microdissected i nvasive lung tumors (22 SCLCs, 21 ADCs, and, 25 SQCs) and 119 noncontiguous foci of histologically normal or hyperplastic epithelia from 10 tumors of each histological type. We determined loss of heterozygosity and microsatel lite alterations at 12 chromosomal regions frequently deleted in lung cance rs using 19 polymorphic microsatellite markers. Our major findings are as f ollows: (a) the mean index of allelic loss in SCLC (0.85) and SQC (0.71) tu mors was higher than that in ADC (0.39) tumors; (b) although there was cons iderable overlap, each tumor type had a characteristic pattern of allelic l oss; (c) most samples of bronchial epithelium accompanying SCLC (90%) had a llelic loss at one or more loci compared with samples accompanying SQC (54% ) or ADC (10%); (d) the mean index of allelic loss was much higher in bronc hial epithelial samples from SCLC (0.27) than in those from SQC (0.08) or A DC (0.01); and (e) although the mean indices of microsatellite alterations in the tumor types were similar, the bronchial epithelial samples accompany ing SCLC had a 10-fold higher mean index (0.063) than those accompanying SQ C (0.006) or ADC (0,006), Our findings indicate that extensive genetic dama ge in the accompanying normal and hyperplastic bronchial epithelium is char acteristic of SCLC tumors and suggest major differences in the pathogenesis of the three major lung cancer types.