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Aberrations in the Fragile Histidine Triad (FHIT) Gene in Idiopathic Pulmonary Fibrosis¹

The Fourth Department of Medicine [K. U., A. Y., A. G., Y. H., K. M., M. S., F. K., K. T., S. Kud.], The Second Department of Surgery [K. K., S. T.], and Department of Pathology [H. M., S. Kun., Y. F.], Nippon Medical School, Tokyo 113-8603, Japan, and Department of Cancer Genetics and Breast Oncology Programs [K. C.], and Thoracic Oncology Laboratory [D. M. J.], University of California-San Francisco Comprehensive Cancer Center, University of California, San Francisco, California 94115

Idiopathic pulmonary fibrosis (IPF) seems to be closely associated with lung carcinogenesis. To identify the genetic characteristics of precancerous IPF lesions in the peripheral lung, we performed PCR-based microsatellite analysis with DNA extracted from microdissected tissues; fluorescent in situ hybridization (FISH) analysis of the fragile histidine triad (FHIT) gene and immunohistochemical analysis of Fhit protein expression in samples of metaplasias and bronchiolar epithelia obtained from patients with IPF. We used four microsatellite markers of the FHIT gene within or flanking the FHIT gene on chromosome 3p for loss of heterozygosity (LOH) analysis. LOH of the FHIT locus was frequently found among the lesions of metaplasias and bronchiolar epithelia in the patients with IPF [62 (52%) of 119 informative lesions]. Fifty-four (73%) of the 74 lesions of metaplasias and bronchiolar epithelia obtained from the IPF patients with lung carcinoma and 8 (17%) of the 46 samples obtained from the IPF patients without lung carcinoma showed LOH at the FHIT gene (P < 0.0001). We confirmed allelic loss in the metaplasias and bronchiolar epithelia of IPF by FISH analysis of the FHIT gene. Additionally, the level of Fhit protein expression in the metaplastic cells of IPF was frequently reduced. Our findings suggest that allelic loss of the FHIT gene may be involved in carcinogenesis in the peripheral lung of patients with IPF.