Genomic Maintenance & Repair

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP333) Dogs at high risk for transitional cell carcinoma exhibit microsatellite instability in tumors.

McNiel, Elizabeth*,1, Madrill, Nicole1, Griffin, Kelly1, Mickelson, James2, 1 Department of Veterinary Clinical Sciences, Saint Paul, MN, USA2 Department of Veterinary and Biomedical Sciences, Saint Paul, MN, USA

ABSTRACT- Introduction and Objectives: DNA microsatellite sequences (MS) are subject to replication errors, which for the most part, are detected and repaired by the mismatch repair (MMR) system. When MMR is defective, MS lesions accumulate, a phenomenon called microsatellite instability (MSI). Defects in MMR contribute to carcinogenesis and can confer inherited cancer susceptibility, as with hereditary nonpolyposis colon cancer (HNPCC) in humans. To better characterize the genetic events in canine carcinogenesis, we have evaluated canine malignancies for MSI. Results: To evaluate MSI, we compared PCR-amplified MS sequences from normal DNA isolated from blood to tumor DNA obtained from paraffin embedded sections. A panel of twenty-two MS loci was evaluated including both tetra- and di- nucleotide repeats. We identified aberrant MS alleles in many malignant epithelial tumors. Most tumors demonstrated low-level MSI, with 1 to 3, primarily tetranucleotide, loci affected. Interestingly, we have demonstrated high-level MSI in a large proportion of transitional cell carcinomas (TCC) of the lower urinary tract. These tumors have aberrations in greater than 30% of MS loci, most of which are dinucleotide repeats. Most of high MSI tumors are from West Highland white terriers, a breed that is roughly four times more likely to develop TCC than other breeds. Conclusions: The pattern of instability in TCC is similar to that observed in HNPCC, a hereditary tumor susceptibility syndrome that includes TCC in the spectrum of tumors occurring in affected individuals. Currently, we are evaluating for defects in the MMR system in West Highland white terriers as a possible mechanism for the development of MSI and tumor susceptibility in the breed. TCC in the West Highland white terrier could be a useful model for studying the role of MSI in carcinogenesis as well as for exploring preventative and therapeutic strategies in individuals with MMR defects.

Key words: microsatellite instability, dna repair, mismatch, canine

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2005 RRS