Chromosomal changes and cytogenetic responses to asbestos have been observed in rodent and human mesothelial cells in culture (51–53). Although human mesothelial cells may be more sensitive to the cytotoxic effects of asbestos than bronchial epithelial cells or fibro-blasts (52), it is unclear whether individual sensitivity to asbestos fibers is due to specific genetic traits. For example, the glutathione-S-trans-ferase M1 (GSTM1) genotypes of patients with mesothelioma suggest that the lack of the GSTM1 gene does not render human mesothelial cells more sensitive to chromosomal damage by amosite asbestos fibers. However, GSTM1 null cells are more susceptible than GSTM1-positive cells to growth inhibitory effects of fibers (54).
A complex profile of somatic genetic changes has been revealed in human malignant mesotheliomas. These changes implicate a multistep process of tumorigenesis. The occurrence of multiple, recurrent cyto-genetic deletions suggests that loss or inactivation of tumor suppressor genes are critical to the development and progression of mesothelioma.
Deletions of specific regions in the short (p) arms of chromosomes 1, 3, and 9 and long (q) arms of 6, 13, 15, and 22q are repeatedly observed, and loss of a copy of chromosome 22 is the single most consistent numerical change (55).
Deletions of specific regions in the short (p) arms of chromosomes 1, 3, and 9 and long (q) arms of 6, 13, 15, and 22q are repeatedly observed, and loss of a copy of chromosome 22 is the single most consistent numerical change (55).
Relatively little is known about the early changes in the genesis of mesothelioma. Of the known cytogenetic changes, the most frequent is loss of p16/CDKN2A-p14ARF
at 9p21(by homozygous deletion) (56), adversely affecting both Rb and p53 pathways, respectively. NF2 (merlin), a tumor suppressor located at 22q12 (by an inactivating muta-
tion coupled with allelic loss) is also frequently altered in mesothe-liomas (57–60). Other conventional proto-oncogenes and tumor suppressor genes have been investigated including N-ras (61), Ha- and Ki-ras (62), and the tumor suppressor gene p53, but no consistently fre-quent mutations have been found (61–63).
Cytogenetic Changes by Asbestos Fibers in Mesothelial Cells and Mesotheliomas
at 9p21(by homozygous deletion) (56), adversely affecting both Rb and p53 pathways, respectively. NF2 (merlin), a tumor suppressor located at 22q12 (by an inactivating muta-
tion coupled with allelic loss) is also frequently altered in mesothe-liomas (57–60). Other conventional proto-oncogenes and tumor suppressor genes have been investigated including N-ras (61), Ha- and Ki-ras (62), and the tumor suppressor gene p53, but no consistently fre-quent mutations have been found (61–63).
Cytogenetic Changes by Asbestos Fibers in Mesothelial Cells and Mesotheliomas
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