Browsing by Author "Mackay, B"

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    Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer
    (AMER ASSOC CANCER RESEARCH, 1999) Wistuba, II; Behrens, C; Virmani, AK; Milchgrub, S; Syed, S; Lam, S; Mackay, B; Minna, JD; Gazdar, AF
    Allelic Losses on the short arm of chromosome 8 (8p) have been reported as frequent events in several cancers, including Lung. However, no comprehensive mapping analysis of chromosome 8p in Lung cancer tumors has been performed, and no data are available about the stage at which these abnormalities occur during the multistage development of lung cancer. Using 26 microsatellite markers, we mapped the chromosome 8 regions frequently deleted in lung cancer in 13 small cell carcinoma and 17 non-small cell lung carcinoma cell Lines and in 68 microdissected archival primary lung tumors (22 small cell lung carcinomas, 25 squamous cell carcinomas, and 21 adenocarcinomas), We also studied the role of 8p deletions in lung cancer pathogenesis by examining 95 microdissected normal epithelium and preneoplastic samples from 11 surgically resected squamous cell Lung carcinomas and from 58 bronchoscopy biopsy samples obtained from 31 current and former smokers. High frequencies of deletions at 8p21-23 regions were detected in lung cancer cell lines and in primary lung tumors. Deletions commenced early during the multistage development of lung cancer at the hyperplasia/metaplasia stage in cancer patients and in smokers without cancer. Allelic deletions persisted for up to 48 years after smoking cessation. There was a progressive increase of the overall 8p21-23 loss of heterozygosity frequency and in the size of the deleted region with increasing severity of histopathological preneoplastic changes. In epithelial samples from resected squamous cell Lung carcinomas, we compared the presence of loss of heterozygosity at 8p21-23 with deletions at chromosomes 3p and 9p, Of interest, the pattern of deletions was not random, and 8p21-23 allelic Losses always followed 3p deletions and usually followed 9p deletions. We conclude that 8p21-23 deletions are frequent and early events in the pathogenesis of Lung carcinomas.
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    Molecular changes in the bronchial epithelium of patients with small cell lung cancer
    (AMER ASSOC CANCER RESEARCH, 2000) Wistuba, II; Berry, J; Behrens, C; Maitra, A; Shivapurkar, N; Milchgrub, S; Mackay, B; Minna, JD; Gazdar, AF
    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)I, 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.