Abstract
Asbestos is a well-known lung cancer-causing mineral fiber. In vitro and in vivo experiments have shown that asbestos can cause chromosomal damage and aberrations. Lung tumors, in general, have several recurrently amplified and deleted chromosomal regions. To investigate whether a distinct chromosomal aberration profile could be detected in the lung tumors of heavily asbestos-exposed patients, we analyzed the copy number profiles of 14 lung tumors from highly asbestos-exposed patients and 14 matched tumors from nonexposed patients using classic comparative genomic hybridization (CGH). A specific profile could lead to identification of the underlying genes that may act as mediators of tumor formation and progression. In addition, array CGH analyses on cDNA microarrays (13,000 clones) were carried out on 20 of the same patients. Classic CGH showed, on average, more aberrations in asbestos-exposed than in nonexposed patients, and an altered region in chromosome 2 seemed to occur more frequently in the asbestos-exposed patients. Array CGH revealed aberrations in 18 regions that were significantly associated with either of the two groups. The most significant regions were 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2, and 19p13.1-p13.3 (P < 0.005). Furthermore, 11 fragile sites coincided with the 18 asbestos-associated regions (P = 0.08), which may imply preferentially caused DNA damage at these sites. Our findings are the first evidence, indicating that asbestos exposure may produce a specific DNA damage profile.
Highlights
Several risk factors are assumed to be associated with lung cancer initiation and tumor development
Tobacco smoking is clearly the most important cause of lung cancer, accounting for f80% to 90% of all cases in males and f50% to 80% among females [1], whereas the etiologic fraction of asbestos exposure in lung cancer among men ranges from 6% to 23% in different studies
The exposed group consisted of persons who had both a definite or probable exposure according to the work history and a pulmonary asbestos fiber count >5 million fibers per gram dry weight
Summary
Several risk factors are assumed to be associated with lung cancer initiation and tumor development. We report investigation of gene copy number changes specific to asbestos-exposed lung cancer patients using classic and array CGHs, leading for the first time to identification of a genomewide profile of aberrations in lung tumors of asbestos-exposed patients. To identify exposure-related aberrations, the array CGH data from individual patients were analyzed at group level by comparing gene copy number ratios of the tumors of exposed and nonexposed patients.
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