The FHIT gene in oral squamous cell carcinoma: allelic imbalance is frequent but cDNA aberrations are uncommon.

The FHIT (fragile histidine triad) gene at chromosome 3p14.2 spans the FRA3B fragile site and encodes for a diadenosine triphosphate hydrolase-type protein. FHIT is frequently abnormal in solid tumours including those of the upper aerodigestive tract (UAT) and has therefore been proposed as a tumour-suppressor gene. This proposition was evaluated here for oral squamous cell carcinoma (SCC) using microsatellite analysis, reverse transcription-polymerase chain reaction (RT-PCR), FHIT exon 5 PCR and direct sequencing. Fifty-eight primary oral SCCs were examined with two FHIT gene microsatellite markers (D3S4103 and D3S1300) and two markers flanking FHIT. Allelic imbalance (AI) occurred in 28 of 52 informative cases (54%) at one or both FHIT markers (D3S4103: 53%; D3S1300: 42%). A significant association was noted between frequency of AI and advanced stage tumours for D3S4103 but not between AI frequency and smoking. AI frequency at D3S1300 and at a flanking marker correlated with low survival. Of eight oral/UAT SCC cell lines examined, six produced abundant wild-type transcript and one yielded mostly truncated transcripts, the most abundant of which lacked exons 5-7. A double deletion was also detected in one of 11 primary oral SCCs. Our microsatellite assay results show that the FHIT gene is frequently disrupted in oral SCC. However, as FHIT was shown to be expressed normally in the great majority of oral/UAT SCCs studied, its likely involvement in the molecular pathogenesis of the disease as a tumour suppressor remains doubtful.