Novel tumor suppressor locus in human chromosome region 3p14.2

Background: Alterations of chromosome region 3p14 are observed in numerous human malignancies. Because the pattern of allelic losses suggests the exis tence of at least one tumor suppressor gene within this region, we establis hed a library of yeast artificial chromosomes (YACs) containing contiguous human 3p14 sequences to permit a search for tumor suppressor loci within th e 3p14 region by use of functional complementation. Methods: YACs specific for human chromosome region 3p14 were transduced by spheroplast fusion into cells of the human nonpapillary renal carcinoma cell line RCC-1, which sho ws a cytogenetically detectable 3p deletion and is tumorigenic in nude mice . Results: We identified a 3p14.2-specific YAC clone, located in the vicini ty of the fragile histidine triad (FHIT) gene (but toward the telomere), th at is capable of inducing sustained suppression of tumorigenicity in nude m ice and of activating cellular senescence in vitro. Among 23 mice given inj ections of RCC-1 cells containing this YAC, 16 (70%) remained tumor free fo r at least 6 months, whereas tumor formation occurred after a median of 6 w eeks in control mice given injections of either RCC-1 parental cells or a r evertant cell line tin which the YAC had lost all human sequences) or RCC-1 parental cells containing other, unrelated YACs, Similar results were obta ined following microcell-mediated transfer of the entire human chromosome 3 , Conclusion: These data provide strong evidence for the existence of a nov el tumor suppressor locus adjacent to the previously identified candidate t umor suppressor gene, FHIT, in 3p14.2. Positional cloning of the novel supp ressor element within the 3p14.2-specific YAC and the sequence's molecular and functional characterization should add to the understanding of the path ogenesis of renal cell carcinoma and other human tumors that exhibit 3p14 a berrations.