LOSS OF FHIT EXPRESSION IN GASTRIC-CARCINOMA

Loss of heterozygosity involving the short arm of chromosome 3 has bee n reported in gastric and other human tumors. We have cloned and mappe d a candidate tumor suppressor gene, FHIT (fragile histidine triad), t o this chromosomal region (3p14.2). To investigate the role of FHIT ge ne alterations in the development of gastric carcinoma, we examined 8 gastric carcinoma-derived cell lines and 32 primary adenocarcinoma sam ples by Southern blot analysis. We also analyzed the integrity of FHIT transcripts by reverse transcription-PCR. The occurrence of alteratio ns in the FHIT gene and its transcript correlated with the absence of Fhit protein expression by immunoblot analysis in the cancer cell line s. Four of eight cell lines showed deletion or rearrangement within th e FHIT gene, together with the absence of the wild-type transcript and the Fhit protein. Among the primary gastric carcinomas, rearrangement of the FHIT gene and/or aberrant reverse transcription-PCR products w ere detected in 17 of 32 (53%) tumors, and 20 of 30 (67%) samples exhi bited an absence of Fhit protein expression. Gastric cancer is thought to develop from carcinogenic exposure, possibly explaining the high f requency of abnormalities in the FHIT gene, a fragile locus exhibiting susceptibility to carcinogen-induced alterations. The consequent abse nce or reduction of Fhit protein expression is consistent with the pro posal that the FHIT gene is a preferential target of environmental car cinogens and that FHIT inactivation plays a role in the development of gastric cancer.