title: Loss of Fhit is frequent in stage I non-small cell lung cancer and in the lungs of chronic smokers.
abstract: Abnormalities of FHIT, a candidate tumor suppressor gene at 3p14.2, have been found frequently in multiple tumor types including non-small cell lung cancer (NSCLC). To investigate whether FHIT inactivation plays a role in early lung tumorigenesis, Fhit levels were determined by immunohistochemistry in tumors from 87 patients with stage I NSCLC and in 372 bronchial biopsy specimens from 86 chronic smokers without evidence of malignancy. We found that 49% of NSCLC specimens demonstrated significantly decreased staining or lack of staining for Fhit. However, Fhit expression status was not significantly associated with disease-free survival or overall survival. Analysis of a subset of 76 specimens on which microsatellite analysis at the FHIT locus was performed did not show a strong association between loss of heterozygosity at FHIT and Fhit expression, suggesting the presence of complex mechanisms of Fhit inactivation. Of 372 bronchial biopsies from chronic smokers, 86 biopsies (23%) exhibited decreased Fhit expression or lack of Fhit expression. In 37 of 86 (43%) subjects, decreased Fhit expression or lack of expression was observed in at least one biopsy site. Loss of Fhit expression was significantly higher in bronchial metaplastic lesions (23 of 49 lesions, 47%) than in histologically normal bronchial epithelium (63 of 323 specimens, 20%; P < 0.001). Smokers with a metaplasia index of > 15% had a higher frequency of loss of Fhit expression than those with a metaplasia index of < or = 15% (P = 0.015). Interestingly, current smokers had 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 substantial number of early-stage NSCLC and preneoplastic lesions in chronic smokers. The association between cigarette smoking and Fhit expression suggests a role for FHIT in the initiation of smoking-related lung tumorigenesis.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston 77030, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Tseng
authors.forename: B L
authors.initials: BL
authors.lastname: Kemp
authors.forename: F R
authors.initials: FR
authors.lastname: Khuri
authors.forename: J M
authors.initials: JM
authors.lastname: Kurie
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.forename: W K
authors.initials: WK
authors.lastname: Hong
authors.forename: L
authors.initials: L
authors.lastname: Mao
mesh_terms: D017766:Acid Anhydride Hydrolases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D009367:Neoplasm Staging; D011506:Proteins / Q000235:genetics*; D012907:Smoking / Q000235:genetics* / Q000473:pathology; D015996:Survival Rate; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D011506:Proteins; D000099170:Bis(5'-adenosyl)triphosphatase