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Chromosome Fragile Sites Signature and Genome Instability in Human Epithelial cells

Common chromosome fragile sites (CFSs) are highly sensitive to genotoxic stress and perturbation of replication, resulting in deletions within genes located at these sites. CFSs at 3p14.2, 16q23, 4q, 7q, and 6q are the most frequently expressed in lymphoblasts but CFSs have not yet been mapped in epithelial cells. We are defining CFSs in epithelial cells derived from breast tissue to determine if they represent the sites most frequently altered in cancer cells of epithelial organs from which most human cancers derive. We observed that in MCF10A noncancerous breast epithelial cells, chromosome regions 16q23, 2q, 12q, 1p most frequently exhibited chromosome breaks typical of CFS after aphidicolin treatment. This suggests that, as observed for cells of fibroblast origin, CFSs in epithelia are epigenetically determined. In parallel, we have focused on the role of Fhit protein, encoded at the CFS at 3p14.2, on chromosome stability and association with nucleotide pyrimidine pool imbalance. We investigated chromosome instability in epithelial cells deficient for Fhit expression vs Fhit‐expressing cells and observed increased aneuploidy, sister chromatid exchanges, chromosome breaks and gaps in Fhit‐deficient cells. Moreover, Fhit deficiency leads to thymidine kinase 1 down regulation, resulting in pyrimidine pool disequilibrium and accounting, in part, for genome instability.