Role of Tumor Suppressor Gene Products of Common Fragile Sites in Human Diseases
Common fragile sites (CFSs) are large chromosomal regions identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs stems from their key role in DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was correlated with genome instability in precancerous lesions and during tumor progression. Two opposing views dominate the discussion regarding the role of CFSs. One school of thought suggested that genomic instability during cancer progression causes collateral damage to genes residing within CFSs, such as WWOXand FHIT. These genes are proposed to be unselected ''passenger'' mutations. The counter argument is that deletions and other genomic alterations in CFSs occur early in cancer development. Cancer cells with deletions in genes that span CFSs are then selectively expanded due to loss of tumor suppressor functions such as protection of genome stability, coordination of cell cycle or apoptosis.
Recent observations from our lab clearly suggest that gene products of CFSs play driver roles in cancer transformation. Furthermore, accumulating evidence links some of these products with metabolic diseases and neuropathy. Investigating the role of these gene products in human diseases is a major interest of our lab work. The ultimate goal of our research is hence to discover the genes and to elucidate the pathways that represent targets for the development of rational, specific and effective therapeutic approaches.