Loss of F HIT Expression in Gastric Carcinoma1

Loss of hetcro/ygosity involving the short arm of chromosome 3 has been reported in gastric and other human tumors. We have cloned and mapped a candidate tumor suppressor gene, /•'///'/' (fragile histidine tri ad), to this chromosomal region (3pl4.2). To investigate the role of FHIT gene alterations in the development of gastric carcinoma, we examined 8 gastric carcinoma-derived cell lines and 32 primary adenocarcinoma samples by Southern blot analysis. We also analyzed the integrity of FHIT transcripts by reverse transcription-PCR. The occurrence of alterations in the FHIT gene and its transcript correlated with the absence of Fhit protein expression by immunoblot analysis in the cancer cell lines. Four of eight cell lines showed deletion or rearrangement within the / //// gene, together with the absence of the wild-type transcript and the Fhit protein. Among the primary gastric carcinomas, rearrangement of the F HIT gene and/or aberrant reverse transcription-PCR products were detected in 17 of 32 (53% ) tumors, and 20 of 30 (67%) samples exhibited an absence of Fhit protein expression. Gastric cancer is thought to develop from carci nogenic exposure, possibly explaining the high frequency of abnormalities in the FHIT gene, a fragile locus exhibiting susceptibility to carcinogeninduced alterations. The consequent absence or reduction of Fhit protein expression is consistent with the proposal that the FHIT gene is a prefer ential target of environmental carcinogens and that /•'///'/' inactivation plays a role in the development of gastric cancer.