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[Cancer Research 59, 1973-1979, April 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 1973-1979, April 15, 1999]
© 1999 American Association for Cancer Research

Molecular Biology and Genetics

Allelic Losses at Chromosome 8p21–23 Are Early and Frequent Events in the Pathogenesis of Lung Cancer1

Ignacio I. Wistuba, Carmen Behrens, Arvind K. Virmani, Sara Milchgrub, Salahuddin Syed, Stephen Lam, Bruce Mackay, John D. Minna and Adi F. Gazdar2

Hamon Center for Therapeutic Oncology Research [I. I. W., C. B., A. K. V., S. S., J. D. M., A. F. G.] and Departments of Pathology [A. K. V., S.M., A. F. G.], Internal Medicine, and Pharmacology [J. D. M.], University of Texas Southwestern Medical Center, Dallas, Texas 75235; Department of Pathology, Pontificia Universidad Catolica de Chile, Santiago, Chile 114-D [I. I. W.]; British Columbia Cancer Agency, Vancouver, British Columbia, Canada [S. L.]; and Department of Pathology, M. D. Anderson Cancer Center, Houston, Texas 77030 [B. M.]

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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Copyright © 1999 by the American Association for Cancer Research.