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Department of Cancer Cell Biology [H. H. N., L. G., K. T. K.] and Department of Environmental Health, Occupational Health Program [H. H. N., L. G., D. C. C., K. T. K.], Harvard School of Public Health, Boston, Massachusetts 02115; Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California 94143 [J. K. W.]; and Pulmonary and Critical Care Unit [D. C. C.] and Thoracic Surgery Unit [J. C. W.], Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
Alterations in the FHIT gene region have been previously associated with smoking status and the occurrence of lung tumors. In the current study, we examined the nature of the mutations that occur at FHIT and the types of carcinogen exposures that are associated with FHIT alterations. We screened 40 primary lung tumors for the presence of point mutations within the coding exons of FHIT using PCr-single-strand conformational polymorphism. Tumors were also analyzed for allelic loss using microsatellite markers located in or near FHIT. No tumors contained point mutations within the coding region of the FHIT gene. However, several samples failed to generate a PCR product, suggesting that regions of the gene are homozygously deleted. Samples were reanalyzed for exon loss using PCR; 13 of 30 tumors failed to generate a PCR product, and 20 of 30 tumors were missing at least one FHIT exon or had loss (loss of heterozygosity or deletion) of one microsatellite marker, suggesting that regions of the gene are homozygously deleted. These data indicate that the FHIT gene has a novel pattern of mutational inactivation not seen previously with other tumor suppressor genes, most likely influenced by the proximity of the FRA3B region. There were no associations of age, sex, p53, or k-ras mutation and FHIT exon deletion. However, there was an association of smoking duration and asbestos exposure with FHIT exon loss, indicating that carcinogenic exposures may be causal in the generation of alterations in the FHIT region.
1 Supported by NIH Grants ES00002, ES/CA06409, CA74386, ES08357, and ES04705.
2 To whom requests for reprints should be addressed, at Department of Cancer Cell Biology, Harvard School of Public Health, Harvard Medical School, 665 Huntington Avenue, Boston, MA 02115-9957.
Received 3/ 4/98. Accepted 3/18/98.
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