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

Abstract

To better understand the pathways involved in the pathogenesis of small cell lung carcinoma (SCLC), we compared the patterns of molecular changes present in these tumors and their accompanying bronchial epithelium with those present in the other two major types of lung cancer [squamous cell carcinoma (SQC) and adenocarcinoma (ADC)]. We obtained DNA from 68 microdissected invasive 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 microsatellite alterations at 12 chromosomal regions frequently deleted in lung cancers using 19 polymorphic microsatellite markers. Our major findings are as follows: (a) the mean index of allelic loss in SCLC (0.85) and SQC (0.71) tumors was higher than that in ADC (0.39) tumors; (b) although there was considerable overlap, each tumor type had a characteristic pattern of allelic loss; (c) most samples of bronchial epithelium accompanying SCLC (90%) had allelic 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 bronchial epithelial samples from SCLC (0.27) than in those from SQC (0.08) or ADC (0.01); and (e) although the mean indices of microsatellite alterations in the tumor types were similar, the bronchial epithelial samples accompanying SCLC had a 10-fold higher mean index (0.063) than those accompanying SQC (0.006) or ADC (0.006). Our findings indicate that extensive genetic damage in the accompanying normal and hyperplastic bronchial epithelium is characteristic of SCLC tumors and suggest major differences in the pathogenesis of the three major lung cancer types.

Fig. 1

Representative autoradiograph of gels demonstrating LOH (closed arrowheads) and MAs (open arrowheads) at five chromosomal regions (3p22–24, 17p13-TP53, 6q16 –21, 5q21–22, and 9p21) in bronchial epithelium and the corresponding lung tumor specimens. There are two examples of MAs [marker D3S1537 (3p22–24) in the SCLC tumor sample and marker D9S1748 (9p21) in the hyperplastic bronchial epithelium]. L, lymphocytes; N, histologically normal bronchial epithelium; H, hyperplastic bronchial epithelium; T, invasive lung tumor. Bars, the main allele bands.

Fig. 2

Overall incidence of allelic loss represented by the FRL-sample index of each (A) invasive lung cancer specimen (n = 68) and (B) histologically normal and hyperplastic bronchial epithelium specimens (n = 119) by histological tumor type. The box at the bottom of the chart in B indicates the number of bronchial epithelial samples with no allelic loss (FRL-sample = 0). Bars and numbers indicate the mean FRL-sample indices for each category.