Microsatellite instability is infrequent in azoxymethane-induced rat intestinal tumors: An assessment by capillary electrophoresis

A rat model of colon cancer in which tumors are induced by azoxymethane (AO M) is frequently used to study putative environmental agents that may modif y the risk of human colon cancer development. In order to evaluate the usef ulness of this model for human risk assessment, a comparison of the molecul ar changes associated with tumorigenesis in the rat model with those in hum an colon cancer is desirable. Microsatellite instability (MSI), an alterati on in length of short repetitive DNA sequences associated with defective DN A mismatch repair, is an important molecular characteristic of many human c olon tumors. Intestinal tumors were induced in male Fischer 344 rats inject ed with 15 mg/kg body wt AOM in four weekly doses. Thirteen intestinal tumo rs were examined for MSI at 10 different microsatellite loci, using a capil lary electrophoresis (CE) method for accurate assessment of DNA length. Thi s method was shown to have a resolution of 1 bp for a 140-bp PCR product an d to be capable of detecting one mutant sequence within a background of 10 wild-type sequences. The CE method also readily distinguished a known MSI-p ositive human tumor sample from its matching control sample. Among the 13 r at intestinal tumors examined, only one had MSI, which was present at only a single locus. We conclude that, unlike sporadic human colon tumors in whi ch 15-30% of tumors have MSI (usually at multiple loci), MSI is very rare i n AOM-induced rat intestinal tumors.