Mutations in Exons 8 and 11 of c-kit Gene in Canine Subcutaneous Mast Cell Tumors and Their Association with Cell Proliferation

SIMPLE SUMMARY: Mast cell tumors (MCTs) are one of the most common skin tumors in dogs with variable clinical behavior ranging from benign lesions to those causing widespread metastasis. Prognostic factors have been intensively studied in cutaneous MCTs but are less commonly investigated in subcutaneous MCTs as the majority are benign. Activating mutations in exons 8 and 11 of c-kit, a gene that regulates proliferation and differentiation of mast cells, occur commonly in canine cutaneous MCTs and are strong predictors of prognosis. c-kit mutations have rarely been reported in subcutaneous MCTs. The goal of this study was to identify the prevalence of c-kit mutations in exons 8 and 11 in 216 canine subcutaneous MCTs and to investigate their association with other prognostic factors, including mitotic count, histologic grade, KIT pattern and proliferation markers. We detected c-kit mutations in exons 8 and 11 in 23 (10.6%) and 12 (5.56%) subcutaneous MCTs, respectively. c-kit mutations in exon 11 were associated with histologic high grade and a high mitotic count, suggesting that these parameters can predict the biological behavior of subcutaneous MCTs in a similar manner as in their cutaneous counterparts. ABSTRACT: The prognostic significance of internal tandem duplication (ITD) mutations in exons 8 and 11 of c-kit has been well-described for canine cutaneous mast cell tumors (MCTs), but c-kit mutations have rarely been reported in subcutaneous MCTs. The objective of this study was to identify the prevalence of ITD mutations in exons 8 and 11 of c-kit in canine subcutaneous MCTs and to investigate its association with histologic grade, KIT pattern, and proliferation markers. ITD mutations in exons 8 and 11 of c-kit, mitotic count, Ki67 index, AgNOR number, Ki67xAgNOR score, KIT pattern, and histologic grade (two-tier system) were retrospectively recorded for 216 dogs with subcutaneous MCTs. ITD mutations in exons 8 and 11 of c-kit were detected in 23 (10.6%) and 12 (5.56%) subcutaneous MCTs, respectively. Exon 11 mutations were significantly associated with Kiupel high grade (p < 0.001) and increased mitotic count (p < 0.001) compared to subcutaneous MCTs with no mutations in exons 8 or 11 (p = 0.002) or subcutaneous MCTs with a mutation in exon 8 (p = 0.001). There was no significant association of either c-kit mutation with KIT patterns or proliferation activity. This study identified a higher prevalence of ITD mutations in exons 8 and 11 of c-kit in subcutaneous MCTs than previously reported. Like their cutaneous counterpart, subcutaneous MCTs with exon 11 mutations were more likely to be histologically high grade and have a higher mitotic count, whereas such associations were not observed in subcutaneous MCTs with exon 8 mutations.