Effect of c-myc over-expression and loss of msh-2 expression on somatic intrachromosomal recombination

The rate at which mutations accumulate in tumour cells is greater than the spontaneous mutation rate in normal cells. Cancers therefore exhibit genomic instability. Somatic intrachromosomal recombination (SICR) is a mechanism which can result in inversions and deletions in the DNA, events which are commonly observed in tumours. Oncogenes and suppressor cancer genes are known to be involved in differentiation, proliferation and apoptosis. Recently, there has been evidence that deregulated cancer genes may themselves play a role in genomic instability. We investigated the role of over-expression of thec-mycproto-oncogene and loss of msh-2 expression on genomic instability using SICR as an endpoint. Tumour model mice with these deregulated cancer genes were bred with pKZ1 mice. pKZ1 mice possess an E.coli lacZ transgene in inverse orientation with respect to a promoter complex. When an inversion occurs in the transgene the lacZ gene can be expressed and the lacZ gene product (β-galactosidase) can be detected histochemically in frozen tissues. We analysed SICR inversion events in spleen and marrow of pKZ1/Eμ-myc, pKZ1/heterozygous msh-2 knockouts and pKZ1/homozygousmsh-2 knockout double transgenics. Compared with their pKZ1 litter-mates a significant 2X increase in SICR frequency was observed in pKZ1/Eμ-mycspleen and marrow and a significant 10X decrease in SICR was observed in the pKZ1/homozygous msh2knockout mice. pKZ1/msh2 heterozygous knockout mice exhibited the same SICR inversion frequency as their pKZ1 littermates. This is the first time that c-myc over-expression has been shown to increase SICR in any system. The reduction that we observed in pKZ1/msh-2homozygous knock-out mice suggests that the msh-2 gene may be important for SICR as well as mismatch repair in vivo.