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Prevalence and importance of internal tandem duplications in exons 11 and 12 of c- kit in mast cell tumors of dogs

Sue DowningVeterinary Cancer Referral Group, 1044 South Robertson Blvd, Los Angeles, CA 90035.

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May B. ChienDepartment of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Philip H. KassDepartment of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Peter F. MooreDepartment of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Cheryl A. LondonDepartment of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Abstract

Objective—To determine the prevalence of activating internal tandem duplications (ITDs) in exons 11 and 12 of c-kit in mast cell tumors (MCTs) of dogs and to correlate these mutations with prognosis.

Sample Population—157 formalin-fixed, paraffinembedded MCTs from dogs in the pathology database of the Veterinary Medical Teaching Hospital at the University of California, Davis.

Procedure—Genomic DNA was isolated from tumor specimens and a polymerase chain reaction procedure was performed to determine whether there were ITDs in exons 11 and 12.

Results—We identified ITDs in 1 of 12 (8%) grade-I, 42 of 119 (35%) grade-II, and 9 of 26 (35%) grade-III tumors (overall prevalence, 52 of 157 [33%]). Logistic regression analysis revealed that the odds of grade-II and -III tumors possessing an ITD were approximately 5 times greater than that for grade-I tumors, although these odds did not differ significantly. Although MCTs possessing an ITD were twice as likely to recur after excision and twice as likely to result in metastasis as those without an ITD, these values also did not differ significantly.

Conclusions and Clinical Relevance—These results provide evidence that ITDs in c-kit occur frequently in MCTs of dogs. The high prevalence of c-kit activating mutations in MCTs of dogs combined with the relative abundance of mast cell disease in dogs provide an ideal naturally developing tumor in which to test the safety and efficacy of novel small-molecule kinase inhibitors such as imatinib mesylate. (Am J Vet Res 2002;63:1718–1723)

Abstract

Objective—To determine the prevalence of activating internal tandem duplications (ITDs) in exons 11 and 12 of c-kit in mast cell tumors (MCTs) of dogs and to correlate these mutations with prognosis.

Sample Population—157 formalin-fixed, paraffinembedded MCTs from dogs in the pathology database of the Veterinary Medical Teaching Hospital at the University of California, Davis.

Procedure—Genomic DNA was isolated from tumor specimens and a polymerase chain reaction procedure was performed to determine whether there were ITDs in exons 11 and 12.

Results—We identified ITDs in 1 of 12 (8%) grade-I, 42 of 119 (35%) grade-II, and 9 of 26 (35%) grade-III tumors (overall prevalence, 52 of 157 [33%]). Logistic regression analysis revealed that the odds of grade-II and -III tumors possessing an ITD were approximately 5 times greater than that for grade-I tumors, although these odds did not differ significantly. Although MCTs possessing an ITD were twice as likely to recur after excision and twice as likely to result in metastasis as those without an ITD, these values also did not differ significantly.

Conclusions and Clinical Relevance—These results provide evidence that ITDs in c-kit occur frequently in MCTs of dogs. The high prevalence of c-kit activating mutations in MCTs of dogs combined with the relative abundance of mast cell disease in dogs provide an ideal naturally developing tumor in which to test the safety and efficacy of novel small-molecule kinase inhibitors such as imatinib mesylate. (Am J Vet Res 2002;63:1718–1723)