FRA3B and other common fragile sites: the weakest links

Abstract

Common fragile sites occur on every human chromosome and are frequently involved in chromosome rearrangements in cancer. There might be genes at these fragile sites that contribute to the development of cancer. There are more than 80 common fragile sites, meaning that we all have these weak links in our chromosomes, although there might be variations in the degrees of fragility among individuals. Common fragile sites can be damaged by exposure to carcinogens, such as those in tobacco smoke. The damage to at least one fragile site — FRA3B — also damages the FHIT gene, which encompasses FRA3B. Damage to FHIT contributes to the growth of cancer cells in the lung, kidney, stomach, bladder and other cancers. Mice that are missing one or both Fhit genes are very susceptible to carcinogen-induced cancers that can be prevented or delayed by treatment with viral vectors carrying the FHIT gene. The WWOX gene at FRA16D is also susceptible to DNA damage, causing alteration of expression of WWOX. Alteration of WWOX expression probably contributes to growth of breast, ovarian and other cancers. Genes at other common fragile sites might also contribute to cancer and should be isolated and studied to uncover their functions in neoplastic disease. It is likely that carcinogen exposure can damage several fragile genes within a single cell, thereby activating one or more oncogenes and inactivating one or more tumour-suppressor genes simultaneously. Deletions, amplifications and translocations at fragile sites are a result of delayed replication by carcinogens or other chemicals within the fragile regions, but there is still much to learn about the induction of fragility, repair or misrepair of the damage, and the consequences to the genes in fragile regions. The functions of the fragile genes FRA3B and WWOX are largely unknown.