Knowledge Bank

FHIT encompasses the fragile site FRA3B on chromosome 3 which can be lost and cause genome-wide DNA instability. This instability can cause the loss or mutation of other caretaker genes such as BRAC1/2 genes which causes a specific mutational signature. The mutation profile of FHIT loss closely resembles the mutational signature 5 which suggests that loss of FHIT could be a marker for cancer development as well as a target for prevention of cancer initiation. Loss of FHIT expression occurs due to replication stress at the FHIT locus, at very low levels, which leads to genome -wide DNA instability in the FHIT deficient cells through the reduced expression of the TK1 gene which is needed for normal DNA replication. Genome instability and mutation accumulation in Fhit-deficient cells in tissue culture can be prevented through supplementation with low dose thymidine in the culture medium. It was tested to determine if low dose thymidine supplementation can prevent genome instability in vivo, reduce mutation accumulation and prevent development of cancerous lesions in Fhit-deficient versus sufficient mice, without causing imbalance of cellular dNTP pools for DNA synthesis, a possible deleterious side-effect. A preclinical mouse model using male and female mice ten weeks of age and 50% each gender made up cohorts, eight mice each, which were FHIT +/+ or +/-. Half of each cohort (4 mice each) were treated with or without thymidine supplementation (1.8 g/kg thymidine). Mice receiving the diet without thymidine are pair-fed to allow ingestion of the same amount as thymidine supplemented mice. The mice were euthanized ten weeks after treatment and the tumor development was examined. Tumor burdens did not appear significantly different between +/+ and +/- mice. Histology must be done to further differentiate the tumor types. The research is innovative in using replacement of the scavenger thymidine pathway in vivo, a pathway lost as a direct result of Fhit loss, to counteract genome instability, a major downstream effect of lost Fhit genome caretaker and tumor suppressor function, and thus restore those functions to prevent tumor development.