Published ahead of print on June 28, 2007, doi:10.1164/rccm.200609-1329OC Am. J. Respir. Crit. Care Med., Volume 176, Number 5, September 2007, 505-512 A more recent version of this article appeared on September 1, 2007
Submitted on September 15, 2006 Spectral Karyotyping Detects Chromosome Damage in Bronchial Cells of Smokers and Cancer PatientsMarileila Varella-Garcia1,1 Department of Medicine, University of Colorado Denver Health Sciences Center, School of Medicine, Denver, CO, USA, 2 Department of Pathology, University of Colorado Denver Health Sciences Center, School of Medicine, Denver, CO, USA, 3 Department of Medicine, University of Colorado Denver Health Sciences Center, School of Medicine, Denver, CO, USA; Department of Pathology, University of Colorado Denver Health Sciences Center, School of Medicine, Denver, CO, USA, 4 Health One Presbyterian St. Luke's Hospital, Denver, CO, USA, 5 Department of Medicine, University of Colorado Denver Health Sciences Center, School of Medicine, Denver, CO, USA; Department of Medicine, Veterans Administration Medical Center, Denver, CO, USA, 6 Department of Surgery, University of Colorado Denver Health Sciences Center, School of Medicine, Denver, CO, USA * To whom correspondence should be addressed. E-mail: wilbur.franklin{at}uchsc.edu.
Rationale: Lung cancer is a multistep process that is preceded and often accompanied by molecular cytogenetic lesions in benign bronchial epithelium, the precise character, extent and timing of which are not well defined. Objectives: In this study we comprehensively defined molecular cytogenetic changes in bronchial cells that may precede lung carcinoma using spectral karyotyping (SKY). Methods: SKY was applied to cultured benign bronchial cells from 43 subjects from high-risk smokers without carcinoma, 14 patients with concurrent lung carcinoma and 14 never-smoker healthy volunteers. Measurements and Main Results: The proportion of cells displaying numerical or structural anomalies/total number of metaphase cells was calculated for each case and was referred to as the chromosomal abnormality index (CAI). Mean CAIs were 15.8%, 10.1% and 0.7% for cancer patients, high risk smokers and never smokers, respectively. Clonal abnormalities were found in 17 (40%) of the high-risk smokers without carcinoma and 7 (50%) of the patients with carcinoma but in none of 14 (0%) never-smokers. Chromosomal gains observed by SKY were confirmed in interphase cultured cells or paraffin sections of biopsy specimens by fluorescence in situ hybridization (FISH) in 11 of 13 cases for which appropriate probes were available. In 6 of 57 high risk or carcinoma patients, identical clonal abnormalities were dispersed at multiple bronchial sites and were admixed with non-clonal cells. Conclusions: Clonal and single cell chromosomal abnormalities are frequent in benign bronchial epithelium during lung carcinogenesis indicating that chromosomal missegregation and other chromosomal rearrangements occur before overt malignancy. Key words: spectral karyotyping, metaphase analysis, chromosomal instability, FISH, lung carcinomas
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