Loss of Fhit is frequent in stage I non-small cell lung cancer and in the lungs of chronic smokers

Abnormalities of FHIT, a candidate tumor suppressor gene at 3p14.2, have be en found frequently in multiple tumor types including non-small cell lung c ancer (NSCLC). To investigate whether FHIT inactivation plays a role in ear ly lung tumorigenesis, Fhit levels were determined by immunohistochemistry in tumors from 87 patients with stage I NSCLC and in 372 branchial biopsy s pecimens from 86 chronic smokers without evidence of malignancy.. me found that 49% of NSCLC specimens demonstrated significantly decreased staining o r lack of staining for Fhit. However, Fhit expression status was not signif icantly associated with disease-free survival or overall survival. Analysis of a subset of 76 specimens on which microsatellite analysis at the FHIT l ocus was performed did not show a strong association between loss of hetero zygosity at FHIT and Fhit expression, suggesting the presence of complex me chanisms of Fhit inactivation, Of 372 bronchial biopsies from chronic smoke rs, 86 biopsies (23%) exhibited decreased Fhit expression or lack of Fhit e xpression. In 37 of 86 (43%) subjects, decreased Fhit expression or lack of expression was observed in at least one biopsy site. Loss of Fhit expressi on was significantly higher in branchial metaplastic lesions (23 of 49 lesi ons, 47%) than in histologically normal branchial epithelium (63 of 323 spe cimens, 20%; P < 0.001). Smokers with a metaplasia index of >15% had a high er frequency of loss of Fhit expression than those with a metaplasia index of less than or equal to 15% (P = 0.015), Interestingly, current smokers ha d a higher rate of loss of Fhit expression than former smokers (P = 0.02). Our data indicate that Fhit expression is significantly reduced in a substa ntial number of early-stage NSCLC and preneoplastic lesions in chronic smok ers. The association between cigarette smoking and Fhit expression suggests a role for FHIT in the initiation of smoking-related lung tumorigenesis.