Genes associated with cancer can affect somatic intrachromosomal recombination early in carcinogenesis

The pKZ1 recombination mutagenesis model has provided a sensitive assay in which to study somatic intrachromosomal recombination (SICR) as a mutation end-point. SICR is associated with non-homologous end-joining (NHEJ) which is one of the major mechanisms for repairing DNA double strand breaks in mammalian cells. SICR results in inversions and deletions of DNA, both of which are common chromosomal changes identified in cancers. We hypothesised that cancer associated genes play a role in formation of chromosomal changes and that the pKZ1 model would provide a system in which such a role could be studied in the initial steps in carcinogenesis. Eμ-myc, Msh2 deficient mice, and transgenic adenocarcinoma of mouse prostate (TRAMP) tumour model mice were bred to pKZ1 mice to produce double transgenic animals. SICR inversion events were scored in mouse tissues prior to evident tumour formation, and compared with endogenous pKZ1 SICR levels. Over-expression of the c-myc proto-oncogene resulted in a significant 2.1-fold increase in SICR in spleen. Loss of Msh2 and expression of the SV40 T antigen in TRAMP mice resulted in a significantly reduced SICR frequency (0.3 of the endogenous frequency in pKZ1 mice) in spleen and prostate respectively. Thus, SICR was affected in all three cancer models. We hypothesise that either an increase or decrease in SICR, in the presence of cancer-associated genes, results from aberrant NHEJ repair of DNA double strand breaks. The data presented here suggest that the pKZ1 model may provide new insights into the effect of cancer-associated genes on chromosomal changes in the early stages of carcinogenesis.