FHIT GENE ALTERATIONS IN ESOPHAGEAL CANCER AND ULCERATIVE-COLITIS (UC)

FHIT (fragile histidine triad gene), a candidate tumor suppressor gene , was recently identified and cloned at chromosome 3p14.2. Alterations of this gene have been reported in a number of primary human tumors, including colorectal, esophageal, gastric and lung carcinomas, However , some reports have found no abnormalities in this gene, We investigat ed a total of 63 primary esophageal tumors, nine esophageal cancer cel l lines and 17 ulcerative colitis-associated neoplasms (UCANs) for alt erations of FHIT, In 13 esophageal tumors, we employed overlapping rev erse transcriptase-PCRs (RT-PCRs) to amplify and sequence the complete open reading frame of FHIT, One of 13 primary esophageal tumors analy sed by RT-PCR expressed no detectable FHIT transcript; the remaining 1 2 expressed normal-sized transcripts with wild-type open reading frame sequences, Tn an additional 50 esophageal tumors, the polymorphic mic rosatellite loci D3S1300 and D3S1313 mere used to evaluate loss of het erozygosity (LOH) at 3p14.2. Eleven of these 50 tumors shelved LOH at one or both loci, Tn all these 11 tumors, genomic PCR and direct seque ncing of FHIT exons 5-9 was performed, This analysis revealed that non e of these 11 primary esophageal tumors contained any alterations in t he FHIT open reading frame or adjacent intron sequences, Finally, amon g 17 UCANs, the in vitro synthesized protein (IVSP) assay detected no truncated protein products, nor were there any abnormalities in size o r DNA sequence of FHIT RT-PCR products, However, in six of nine esopha geal carcinoma cell lines, no FHIT RT-PCR product was detectable using either of the overlapping primer sets, Genomic PCR and direct sequenc ing of exons 5-9, also performed in these nine cell Lines, revealed wi ld-type sequence in eight cell lines; however, one cell Line contained no exon 5 PCR product, This cell Line also lacked detectable FHIT tra nscript. These data suggest that the open reading frame of FHIT is not important in the development or progression of most primary esophagea l carcinomas or UCANs, although lack of expression of the FHIT transcr ipt may be common in esophageal cancer-derived cell Lines, The possibi lity of an additional tumor suppressor gene at chromosome 3p14.2 remai ns to be evaluated.