Cancer-associated genes can affect somatic intrachromosomal recombination early in carcinogenesis

Abstract

The pKZ1 recombination mutagenesis model has provided a sensitive assay where we study somatic intrachromosomal recombination (SICR) as a mutation end-point. SICR is associated with non-homologous end-joining repair of double-strand breaks and can result in chromosomal inversions and deletions, both of which are common chromosomal aberrations identified in cancers. It has been difficult to study the effect of cancer-associated genes on chromosomal changes prior to tumour formation in vivo because of a lack of appropriate test systems. We hypothesised that cancer-associated genes play a role in formation of chromosomal aberrations and that the pKZ1 model would provide a system in which such a role could be studied in the initial steps of carcinogenesis. Transgenic tumour model mice were bred to pKZ1 mice to produce double transgenic animals. SICR inversion events were scored in mouse tissues at an early time, 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 resulted in a significantly reduced SICR frequency (0.3 of the endogenous frequency in pKZ1 mice) in spleen and prostate respectively. Therefore SICR was affected in the case of all three cancer-associated genes studied. We hypothesise that the increase and decrease in SICR in the presence of cancer-associated genes results from incorrect repairing of double-strand breaks. The data presented here suggest that the pKZ1 model may provide a powerful tool for studying the effect of cancer-associated genes on chromosomal changes in the early stages of carcinogenesis.