title: Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer.
abstract: 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.
authors.affiliation: Human Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas 75235-8593, USA.
authors.forename: I I
authors.initials: II
authors.lastname: Wistuba
authors.forename: C
authors.initials: C
authors.lastname: Behrens
authors.forename: A K
authors.initials: AK
authors.lastname: Virmani
authors.forename: S
authors.initials: S
authors.lastname: Milchgrub
authors.forename: S
authors.initials: S
authors.lastname: Syed
authors.forename: S
authors.initials: S
authors.lastname: Lam
authors.forename: B
authors.initials: B
authors.lastname: Mackay
authors.forename: J D
authors.initials: JD
authors.lastname: Minna
authors.forename: A F
authors.initials: AF
authors.lastname: Gazdar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D001980:Bronchi / Q000502:physiology; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D004848:Epithelium / Q000502:physiology; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012907:Smoking / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor