Common fragile sites (CFSs) are large regions of genomic instability present in all individuals and they’re also in primates and mice. There are 90 CFSs throughout the human genome corresponding to regions that are frequently deleted or altered during cancer development. Many of the CFSs have been found to contain extremely large genes such as the 1.49 Mb FHIT gene in FRA3B (3p14.2), the 1.46 Mb GRID2 gene at 4q22.3, the 1.0 Mb WWOX gene in FRA16D (16q23.2) and the 1.38 Mb Parkin gene in FRA6E (6q26). Parkin plays an important role in neurological development as mutations in this gene are found in individuals with autosomal recessive Juvenile Parkinsonism, and loss of GRID2 is associated with specific apoptosis in cerebellar Purkinje cells. Although these genes are derived from some of the most unstable regions in the human genome they are highly evolutionarily conserved and the regions spanning these genes in mice are also CFSs. The large genes and the highly unstable regions may be co-conserved because together they serve an important function within the cell. We’ve examined lists of the largest human genes and found that there are 240 that span greater than 500 Kb of genomic sequence and 40 that span greater than 1.0 Mb. We’ve now found that a number of these are also CFS genes. This includes the 2.3 Mb CNTNAP2 gene (FRA7I- 7q35), the 1.54 Mb Dab1 gene (FRA1B- 1p32.3), the 1.9 Mb LRP1B gene (FRA2F- 2q22.1), the 900 Kb FIP1L1/PDGFRA gene (FRA4B- 4q12), the 700 Kb RORA gene (FRA15A- 15q22.2), and the 650 Kb LARGE gene (FRA22B- 22q12.3). We’ve examined expression of these genes in a panel of 50 cell lines derived from tumors of the breast, prostate, ovary, liver, and pancreas and have found specific patterns of loss of expression (LOE) rather than random loss suggesting that there is specific selection for LOE in different tumors. In addition, we’ve detected aberrant transcripts from many of these genes in different cell lines. Many of these large CFS genes play important roles in neurological development. In mice deletions in Parkin are associated with Quaking(viable), deletions in RORA are associated with Staggerer, frequent spontaneous deletions in GRID2 are found in Lurcher mice and deletions in Dab1 are associated with Scrambler. The observation that so many of the CFS genes are involved in neurological development and that they’re altered during cancer development suggests that cancer may be utilizing important developmental pathways. We are starting to functionally characterize the large CFS genes and have found that many of them are involved in responses to cellular stress. We hypothesize that the CFSs and the large genes co-evolved as a stress response system whose function is to transduce extracellular signals into the appropriate responses. This system is utilized during normal development and may be perverted to play an important role in the development of many different cancers

[Proc Amer Assoc Cancer Res, Volume 46, 2005]