Aberration of FHIT gene is associated with increased tumor proliferation and decreased apoptosis - Clinical evidence in lung and head and neck carcinomas

Background: Human FHIT (fragile histidine triad) gene is highly conserved g ene homologous to a group of genes identified in prokaryotes and eukaryotes . Loss of FHIT function may be important in the development and/or progress ion of various types of cancer. Materials and Methods: We undertook a clinical study to analyze the relatio n between aberrant function of FHIT gene, tumor cell proliferation, and int ensity of apoptosis as well as prognostic output in lung and squamous cell head and neck carcinoma (HNSCC). Status of FHTT gene, expression of p21(waf 1), intensity of apoptosis, and cell proliferation were analyzed in HNSCC a nd lung carcinoma tissues by molecular genetic methods, immunohistochemistr y, [H-3]-thymidine labeling method, and FAC-Scan analysis in frozen and par affin-embedded tissue sections. Results: The majority of the malignant lung and HNSCC lesions displayed abe rrant expression of FHIT gene, followed by low or negative expression of p2 1(waf1), and increased intensity of cell proliferation. Similar results wer e obtained on synchronous combinations of normal, precancerous, and cancero us head and neck tissues. The observed changes increased with progression o f these lesions. We examined tumor and corresponding normal tissue samples for microsatellite markers D3S1300 and D3S4103 to evaluate the loss of hete rozygosity (LOH) at the FHIT gene loci. We found high percentage of LOH in both lung tumors and HNSCC (75% for D3S1300 and 79% for D3S4103 in lung can cer, and 87% for D3S1300 and 78% for D3S4103 in HNSCC). The median survival time of the patients suffering from lung cancer without FHIT protein expre ssion was 22.46 months and that of the patients with FHIT expression 36.04 months. FHIT-negative cases tended to correlate with a worse prognosis, but this was not statistically significant. Median survival time of HNSCC pati ents without FHIT protein expression was 30.86 months and that of the patie nts with FHIT expression was 64.04 months (p < 0.05). Conclusions: Our results show a correlation between aberrant FHIT expressio n, a low rate of apoptosis, and high tumor cell proliferation. Aberrant FHI T gene could be a prognostic marker in lung cancer.