Aberrant fragile histidine triad gene transcripts in primary hepatocellular carcinoma and liver cirrhosis

To determine whether transcriptional alterations of the fragile histidine t riad (FHIT) gene play a role in the development and progression of human he patocellular carcinoma (HCC) we used reverse transcription-PCR to examine m RNA FHIT expression in 28 paired samples of HCC (24 in cirrhotic and 4 in n oncirrhotic livers) and matched noncancerous tissue and in 10 normal livers , We also assessed loss of heterozygosity of the polymorphic D3S1300 micros atellite marker in the intron between exons 5 and 6 of the FHIT gene. Abnor mal FHIT transcripts were detected in 13 cases (46.4%): 10 in the cancerous tissue only, 1 with the same pattern in both cancerous and matched noncanc erous tissue, and 2 in the noncancerous tissue only. The four HCCs that aro se in noncirrhotic liver all showed abnormal FHIT transcripts. No alteratio ns were found in normal livers. Sequence analysis of abnormally sized trans cripts revealed that they were generated by the fusion of exons 3 or 4 with exons 8 or 9, Among the cancerous specimens, one case showed only an abnor mal sized transcript derived from the fusion of exons 4 and 9 in the absenc e of any normal-sized transcript, and another case showed deletion of a seq uence comprised between nucleotides -35 and 399 resulting in an exon 4-9 fu sion not respecting the exons' bounds. Loss of heterozygosity was found in two cases with abnormal FHIT transcripts and in only one case with normal t ranscript. Patients with aberrant FHIT transcripts showed a significantly h igher relapse rate and shorter recurrence time (P = 0.001), This could he r elated to a primary genomic Instability affecting particularly susceptible regions like FRA3B and could be associated with on increasing risk of recur rence without involving a causative role.