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Loss of FHIT function in lung cancer and preinvasive bronchial lesions
G Sozzi1, U Pastorino, L Moiraghi
1Division of Experimental Oncology A, E and Anatomical Pathology, Istituto Nazionale Tumori, Milan, Italy.
Abstract:
We previously cloned and characterized the tumor suppressor gene FHIT (fragile histidine triad) at chromosome 3p14.2 and found that this gene is altered by deletions in human tumors, including lung cancer. To assess the frequency and specificity of inactivation and its relevance in a clinical setting, we have produced antibodies against the Fhit protein and studied its expression in a series of non-small cell lung cancers and normal bronchial mucosa and a spectrum of preinvasive lesions by immunohistochemistry. The data indicate that the loss of Fhit protein is the most frequent alteration in non-small cell lung cancer (73%) and precancerous lesions (93%), is significantly higher in the tumors of smokers (75%) than in those of nonsmokers (39%; P < 0.0005), and is an independent and more frequent event than p53 overexpression in tumors and precancerous lesions (73 versus 46%). The percentage of cases lacking Fhit expression was higher in the squamous type compared to adenocarcinoma (87 versus 57%; P < 0.00001), whereas other histotypes (large cell, mucoepidermal) showed an intermediate value (69%). Loss of Fhit expression in a very high percentage of primary lung carcinomas and precancerous lesions supports the notion that FHIT alterations play an important role in the growth control of bronchial cells. FHIT inactivation is particularly important in squamous cell carcinomas that are often associated with precursor dysplastic lesions. The overall high frequency and precocity of Fhit loss in lung carcinogenesis and the development of the presently described immunohistochemical approach suggest a potential use of this gene in the early detection of lung cancer and in chemopreventive studies as an intermediate biomarker.
Insights
Loss of the tumor suppressor gene FHIT (fragile histidine triad) is frequent in lung cancer and precancerous lesions, especially in smokers and squamous cell types. This suggests FHIT alterations are key in lung carcinogenesis and may aid early detection.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The fragile histidine triad (FHIT) gene, a tumor suppressor, is located at chromosome 3p14.2.
- Deletions and alterations in the FHIT gene have been observed in various human tumors, including lung cancer.
Purpose of the Study:
- To determine the frequency and specificity of FHIT gene inactivation in non-small cell lung cancer (NSCLC).
- To assess the clinical relevance of FHIT protein loss in lung carcinogenesis.
- To evaluate FHIT expression as a potential biomarker for early lung cancer detection and chemoprevention.
Main Methods:
- Production of antibodies against the Fhit protein.
- Immunohistochemical analysis of Fhit protein expression in NSCLC, normal bronchial mucosa, and preinvasive lesions.
- Statistical analysis to compare FHIT loss with smoking status, histotype, and p53 overexpression.
Main Results:
- Loss of Fhit protein expression was observed in 73% of NSCLC and 93% of precancerous lesions.
- Fhit loss was significantly higher in smokers (75%) compared to nonsmokers (39%).
- FHIT inactivation (73%) was more frequent and independent of p53 overexpression (46%) in tumors and pre-cancerous lesions.
- Squamous cell carcinomas showed a higher percentage of Fhit loss (87%) compared to adenocarcinomas (57%).
Conclusions:
- Loss of FHIT expression is a frequent and early event in lung carcinogenesis, particularly in squamous cell carcinomas.
- FHIT alterations play a significant role in the growth control of bronchial cells.
- The immunohistochemical detection of Fhit loss may serve as a valuable biomarker for early lung cancer detection and chemoprevention strategies.