AN FHIT TUMOR-SUPPRESSOR GENE

The FRA3B at 3p14.2 is the most common of the constitutive aphidicolin -inducible fragile sites. Using independent approaches, four groups of investigators have cloned and characterized this fragile site. The re sults of these studies have revealed that the FRA3B differs from other heretofore cloned rare fragile sites. First, instability as manifeste d by chromosome breakage occurs over a large region of DNA, encompassi ng at least 500 kb. Second, sequence analysis has not revealed trinucl eotide repeat motifs, characteristic of the rare fragile sites. In add ition to containing the FRA3B, band 3p 14 is also likely to contain a tumor suppressor gene, as evidenced by the presence of deletions, rear rangements, and allele loss in a variety of human tumors, including lu ng, renal, nasopharyngeal, cervical, and breast carcinomas. The recent ly cloned FHIT gene in 3p14.2 is a promising candidate tumor suppresso r gene, since aberrant FHIT transcripts have been found in a significa nt proportion of cancer-derived cell lines and primary tumors of the d igestive and respiratory tracts. Nonetheless, several lines of evidenc e garnered over the past year have called into question the role of FH IT as a classical tumor suppressor gene, and raised the question of wh ether its apparent involvement simply reflects its location within an unstable region of the genome. In the following study, we have summari zed the evidence in support of FHIT as a tumor suppressor gene as well as evidence against such a role, and the experimental evidence needed to demonstrate that FHIT functions as a tumor suppressor gene in the pathogenesis of human tumors. The paradigm of FHIT emphasizes that con firming the role of a candidate tumor suppressor gene may prove diffic ult, particularly for those genes that are located in genetically unst able regions. (C) 1998 Wiley-Liss, Inc.