CHROMOSOME 3P14 ALTERATIONS IN LUNG-CANCER - EVIDENCE THAT FHIT EXON DELETION IS A TARGET OF TOBACCO CARCINOGENS AND ASBESTOS

Alterations in the FRIT gene region have been previously associated wi th smoking status and the occurrence of lung tumors. In the current st udy, we examined the nature of the mutations that occur at FHIT and th e types of carcinogen exposures that are associated with FHIT alterati ons. We screened 40 primary lung tumors for the presence of point muta tions within the coding exons of FHIT using PCR-single-strand conforma tional polymorphism. Tumors were also analyzed for allelic loss using microsatellite markers located in or near FRIT. No tumors contained po int mutations within the coding region of the FHIT gene. However, seve ral 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 markers suggesti ng that regions of the gene are homozygously deleted. These data indic ate that the FHIT gene has a novel pattern of mutational inactivation not seen previously with other tumor suppressor genes, most likely inf luenced by the proximity of the FRA3B region. There were no associatio ns of age, sex, p53, or k-ras mutation and FHIT exon deletion. However , there if as an association of smoking duration and asbestos exposure with FHIT exon loss, indicating that carcinogenic exposures may be ca usal in the generation of alterations in the FHIT region.