The role of deletions at the FRA3B/FHIT locus in carcinogenesis

The FHIT gene, which encodes a 1-kb message and a 16.8-kDa protein that hydrolyses diadenosine triphosphate (ApppA) to ADP and AMP in vitro, covers a megabase genomic region at chromosome band 3p14.2. The gene encompasses the most active of the common human chromosomal fragile regions, FRA3B. Over the years, it has been suggested that fragile sites might be especially susceptible to carcinogen damage and that chromosomal regions of nonrandom alterations in cancer cells may coincide with defined fragile sites. Within the FRA3B region, the characteristic induced chromosome gaps can occur across the entire region, but 60% of the gaps are centered on a 300-kb region flanking FHIT exon 5, the first protein-coding exon. Numerous hemizygous and homozygous deletions, translocations and DNA insertions occur within FHIT in cancer cell lines, uncultured tumors, and even in preneoplastic lesions, especially in tissues such as lung that are targets of carcinogens. This supports the proposed cancer-fragile site connection and suggests that the FHIT gene, expression of which is frequently altered in cells showing FHIT locus damage, is a tumor suppressor gene whose inactivation may drive clonal expansion of preneoplastic and neoplastic cells. Replacement of Fhit expression in Fhit-negative cancer cells abrogates their tumorigenicity in nude mice. Analysis of the approximately 300-kb DNA sequence encompassing FHIT exon 5 in the FRA3B epicenter has provided clues to the mechanism of repair of the fragile site double strand breaks. The mechanism involves recombination between LINE 1 elements with deletion of the intervening sequence, often including FHIT exons. These studies have also shown that FHIT alterations generally entail independent deletion of both FHIT alleles. Future studies will focus on two objectives: study of (1) the in vivo function of the Fhit protein and (2) mechanisms of break and repair in the FRA3B fragile region.