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The fragile histidine triad (FHIT) gene is a bonafide tumor-suppressor gene present on the short arm of chromosome 3 and its loss of function has been evaluated in different types of cancers. Loss of heterozygosity at various sections of the FHIT gene and the methylation analysis of the promoter region showed that it is one of the important and preliminary genetic alterations in the cell, and its restoration in the cell line or nude mice suppresses tumorigenicity. Current research on the FHIT gene has depicted that Fhit interacts with different proteins through different pathways in the nucleus, mitochondria, and cytoplasm, directing the cell to apoptosis.

The fragile histidine triad (FHIT) gene located at the 3p14.2 locus plays an important role in the pathogenesis of lung cancer. The objective of this study was to analyze loss of heterozygosity and FHIT gene methylation status and correlate them to fhit expression. Bronchoscopically obtained lung biopsies from 30 cases of histologically proven carcinoma of the lung in stage III were assessed for the alterations in the FHIT gene. Fhit protein expression was determined by immunohistochemistry, and transcript levels were determined by reverse transcription-PCR. Microsattelite alterations and methylation status of the Fhit gene promoter was determined by PCR. Loss of heterozygosity at the 3p14 locus was observed in all the 30 cases at least by one of the three microsatellite polymorphic markers. The FHIT gene promoter showed complete methylation in 37% cases and partial methylation in 47% cases, and 16% cases showed no promoter methylation. FHIT full-length coding region (exons 5-9) transcripts were present in eight cases (26.6%), and aberrant transcripts were additionally seen in four cases. Loss of FHIT mRNA expression correlated to FHIT promoter methylation but not to loss of heterozygosity at the 3p14 locus. There was a strong correlation between the expression of FHIT at the transcript and protein level. The apoptotic index estimated by the terminal deoxynucleotidyl transferase -mediated nick end labeling assay was significantly correlated to the fhit protein expression. The results of this study indicate that in locally advanced carcinoma of the lung, there is frequent loss of FHIT expression, and methylation of the FHIT gene promoter is an important mechanism of its inactivation. (Mol Cancer Res 2006;4(2):93 -9)

Background: In recent times, the possibility of detecting lung cancer using microsatellite alterations (microsatellite instability and loss of heterozygosity) in DNA of bronchial washings has been explored. However, no data regarding the presence of microsatellite alterations in lung cancer are available from India, a country which contributes significantly to the lung cancer burden of the world. Methods: Bronchial washings as well as tumor specimens obtained on bronchoscopy were analyzed for the presence of loss of heterozygosity (LOH) and microsatellite instability (MSI) using the D3S1300 microsatellite marker on chromosome 3p and the TP53 marker on chromosome 17p. Results: The sensitivities of the TP53 and D3S1300 loci in bronchial washings were 35% and 45% (combined 50%), respectively, which was significantly better than conventional cytology (positive for malignant cells in 15%). The presence of these microsatellite alterations was not related to the age, cumulative smoking exposure or smoking status (current or former) of patients. Conclusion: Microsatellite alterations, particularly LOH, occur in a significant proportion of Indian patients with squamous cell carcinoma of the lung.

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