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Deletions of Chromosome 4 at Multiple Sites Are Frequent in Malignant Mesothelioma and Small Cell Lung Carcinoma¹

Hamon Center for Therapeutic Oncology Research [N. S., A. K. V., I. I. W., J. D. M., A. F. G.] and Departments of Pathology [A. K. V., S. M., A. F. G.], Internal Medicine [J. D. M.], and Pharmacology [J. D. M.], University of Texas Southwestern Medical Center, Dallas, Texas 75235, and Department of Pathology, M. D. Anderson Cancer Center, Houston, Texas 77030 [B. M.]

Recent allelotyping studies suggest that allelic losses at one or both arms of chromosome 4 are frequent in several tumor types. Cytogenetic studies of malignant mesothelioma (MM) and comparative genomic hybridization analyses of small cell lung carcinoma (SCLC) suggest that chromosome 4 deletions may also play a role in these tumor types, although these results have not been confirmed by allelotyping. In an effort to more precisely identify and map the locations of putative tumor suppressor gene(s) on chromosome 4 involved in the pathogenesis of these tumors, we performed loss of heterozygosity studies using 16 polymorphic microsatellite markers. After precise microdissection of archival surgical cases, we studied DNA obtained from 20 MMs, 21 SCLCs, and 20 non-SCLCs (NSCLCs). In addition, DNA from 14 SCLC and 17 NSCLC cell lines and corresponding B lymphoblastoid lines were studied. In MM and SCLC, we observed frequent losses at three nonoverlapping regions: (a) 4q33–34 (region R1; >80%); (b) 4q25–26 (region R2; >60%); and (c) 4p15.1–15.3 (region R3; >50%). Losses at these sites occurred at lower frequencies in NSCLC (>20–30%). Data from tumors and cell lines were similar. In MM and SCLC, the most frequently observed pattern was loss at all three regions. However, in NSCLC, the most frequent pattern was loss at R3 alone. Our study has delineated three nonoverlapping regions of frequent deletions on chromosome 4 in MM and SCLC, suggesting that there may be three putative suppressor genes on chromosome 4, the inactivation of which may be important in the pathogenesis of these tumor types.

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