Concordance of c‐kit Mutational Status in Matched Primary and Metastatic Cutaneous Canine Mast Cell Tumors at Baseline

Abstract

BackgroundMutation analysis of proto‐oncogene c‐kit (c‐kit) is advisable before starting treatment with tyrosine kinase inhibitors in dogs with mast cell tumor (MCT), including those with metastatic disease. Testing is usually performed on primary tumors, assuming that c‐kit mutation status does not change in metastasis.Hypothesis/ObjectivesTo give an insight into the mutational processes and to make a recommendation on the use of c‐kit mutational analysis in the clinical setting.AnimalsTwenty‐one client‐owned dogs with metastatic MCT.MethodsDogs undergoing resection or biopsy for both primary and matched metastatic MCT were prospectively enrolled. Total RNA or DNA was extracted from primary MCT and corresponding metastases. Exons 8, 9, and 11 were amplified by PCR and sequenced. Genetic features between primary MCT and metastases were compared. Their correlation with clinicopathologic features was investigated.ResultsConcordance (mutated or wild‐type) of mutational status, evaluable in 21 primary and matched metastatic (20 nodal and 1 splenic) MCTs, was 100%. Three new c‐kit mutations were identified. No significant correlation was detected between c‐kit mutation and clinicopathologic features.Conclusions and Clinical ImportanceProto‐oncogene c‐kit mutational status is conserved between any primary and its matched secondary tumor, suggesting that both can be used for c‐kit mutational testing. Targeted therapies might be also used to treat metastatic disease.

Comparative aspects of mast cell neoplasia in animals and the role of KIT in prognosis and treatment

“…Studies also document over 80 other nucleotide substitutions and frameshift mutations in neoplastic mast cells from these species, although these have not been confirmed to be Kit activating. While some identified nucleotide substitutions are silent or species‐specific, many result in non‐conservative amino acid changes and hence, may contribute to mast cell malignancy (Giantin et al, ; Haenisch et al, ; Hahn et al, ; Isotani et al, ; Letard et al, ; Marconato et al, ; Nakano, Kobayashi, Bonkobara, & Takanosu, ; Sabattini et al, ; Takeuchi et al, ; Zemke et al, ).…”

“…Between 8% and 29% of canine MCTs carry a regulatory‐type mutation in exon 8, 9 or 11 (Giantin et al, ; Hahn et al, ; Horta et al, ; Letard et al, ; Marconato et al, ; Mochizuki, Thomas, Moroff, & Breen, ). Exon 11 internal tandem duplications (ITDs) comprise 60%–74% of these mutations and are prevalent in 18% of tumours (Giantin et al, ; Hahn et al, ; Letard et al, ; Marconato et al, ; Mochizuki, Thomas, et al, ; Webster et al, ). KIT mutation frequency increases with increasing tumour histological grade and exon 11 ITDs are associated with decreased survival times and the increased chance of tumour recurrence and metastasis (Table ) (Downing et al, ; Horta et al, ; Letard et al, ; Tamlin et al, ).…”

Dysregulation of tyrosine kinases and use of imatinib in small animal practice

“…In humans, the presence of intratumoral genetic heterogeneity influences therapeutic response and contributes to resistance against kinase inhibitors (Bedard et al, 2013). However, in dogs, Marconato et al (2014) observed no difference in the mutation status of KIT between primary canine MCTs and their corresponding metastases. In contrast, Amagai et al (2013) reported that two cases of canine MCT had an ITD mutation in the primary lesion but not in the secondary lesion.…”

Advanced Diagnostic Techniques

“…17-17). C-kit mutation status has also been used to show that when patients develop mast cell tumor recurrence, or multiple mast cells at different sites, those mast cells are derived from the same clone because they harbor the same type of mutation (Marconato et al, 2014;Zavodovskaya et al, 2004). The internal tandem duplication in exon 8 is always the same, an addition of 12 bases.…”