A Study of Mutations in the <i>c-kit</i> Gene of 32 Dogs with Mastocytoma

Riva, Federica; Brizzola, Stefano; Stefanello, D.; Crema, Simone; Turin, Lauretta

doi:10.1177/104063870501700416

Cited by 38 publications

(36 citation statements)

References 7 publications

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“…Of the mutations in exon 11, most (25 of 32) were ITDs. This high frequency of ITDs in exon 11 agrees with previous findings in canine mast cell tumors (5,6,8,21), although the overall distribution of mutations contrasts with that in human mastocytosis, where mutations in exon 17 (i.e., codon 816) are found in the majority of cases and mutations in exon 11 are rare (1). 8 Further analysis of the specific sites of the mutations within exon 11 reveals two hotspots, one between residues 555 and 559 and a second between residues 571 and 590 (Fig.…”

Section: Discussionsupporting

confidence: 78%

Gain-of-Function Mutations in the Extracellular Domain of KIT Are Common in Canine Mast Cell Tumors

Letard

Yang

Hanssens

et al. 2008

Molecular Cancer Research

159

241

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In the current study, we examined the types and frequency of KIT mutations in mast cell tumors from 191 dogs. Sequencing of reverse transcription-PCR products revealed alterations in 50 (26.2%) of the dogs. Most mutations were in exon 11 (n = 32), and of these, most were internal tandem duplications (n = 25) between residues 571 and 590. Within exon 11, there were two hotspots for mutations at codons 555-559 and 571-590. In addition, nine dogs had mutations in exon 8 and eight had mutations in exon 9. We selected the two most common mutants and two representative exon 11 mutants for further analysis. When expressed in Ba/F3 cells, they were constitutively tyrosine phosphorylated and induced growth factor -independent cell proliferation. AG1296, a tyrosine kinase inhibitor, dose dependently inhibited both the tyrosine phosphorylation of these mutants and their induction of growth factor -independent proliferation. This study shows that activating mutations in not only exon 11 but also exons 8 and 9 are common in canine mast cell tumors. These results also show that Ba/F3 cells can be used for the direct characterization of canine KIT mutants, eliminating the need to make equivalent mutations in the mouse or human genes.

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Section: Discussionsupporting

confidence: 78%

Gain-of-Function Mutations in the Extracellular Domain of KIT Are Common in Canine Mast Cell Tumors

Letard

Yang

Hanssens

et al. 2008

Molecular Cancer Research

159

241

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“…In previous studies, the incidence of c-KIT mutations has varied dramatically from 3 to 33%. 13,48,66,71 As previously discussed, this variation likely represents variations in study populations. 66 The highest incidence of c-KIT mutations has been identified in cases of treated-at-referral oncology practices, 13 which are likely to consist of a higher proportion of malignant MCTs.…”

Section: Discussionmentioning

confidence: 96%

Cellular Proliferation in Canine Cutaneous Mast Cell Tumors: Associations with c-KIT and Its Role in Prognostication

et al. 2007

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Abstract. Canine cutaneous mast cell tumor (MCT) is a common neoplastic disease in dogs. Due to the prevalence of canine MCTs and the variable biologic behavior of this disease, accurate prognostication and a thorough understanding of MCT biology are critical for the treatment of this disease. The goals of this study were to evaluate and compare the utility of the proliferation markers Ki67, proliferating cell nuclear antigen (PCNA), and argyrophilic nucleolar organizing region (AgNOR) as independent prognostic markers for canine MCTs and to evaluate the use of these markers in combination, as each marker assesses different aspects of cellular proliferation. An additional goal of this study was to evaluate the associations between cellular proliferation and c-KIT mutations and between cellular proliferation and aberrant KIT protein localization in canine MCTs. Fifty-six MCTs treated with surgical excision alone were included in this study. Each MCT was evaluated for Ki67 expression, PCNA expression, and KIT protein localization using immunohistochemistry; for AgNOR counts using histochemical staining; and for the presence of internal tandem duplication c-KIT mutations using polymerase chain reaction amplification. In this study, increased Ki67 and AgNOR counts were both associated with significantly decreased survival. On the basis of these results, we recommend that the evaluation of cellular proliferation, including evaluations of both Ki67 expression and AgNORs, should be routinely used in the prognostication of canine MCTs. Additionally, the results of this study show that MCTs with aberrant KIT protein localization or internal tandem duplication c-KIT mutations are associated with increased cellular proliferation, further suggesting a role for c-KIT in the progression of canine MCTs.

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“…20,22,27 The presence of aberrant cytoplasmic KIT localization has been correlated with a reduced post-surgical survival. 10,25 A large number of c-KIT mutations have been identified in canine MCTs, mostly localized in exon 11, 8,15,19,29,38,40,42 occasionally in exons 8 and 9, 15 and sometimes in exon 17.…”

Section: Introductionmentioning

confidence: 99%

c-KIT messenger RNA and protein expression and mutations in canine cutaneous mast cell tumors

et al. 2011

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Abstract. Cutaneous mast cell tumors (MCTs) are among the most common neoplasms in dogs and show a highly variable biologic behavior. Histological grading, cell proliferation markers, and KIT immunohistochemistry are typically used to predict post-surgical prognosis. In the present study, c-KIT messenger RNA (mRNA) expression was measured in canine MCTs and its relationship with tumor grade, immunohistochemical staining pattern, post-surgical prognosis, and mutations was investigated. A significant increase of c-KIT mRNA was observed in MCTs versus healthy skin and surgical margins. Mutations were observed in 8.3% of cases. The KIT staining pattern was investigated for both grading systems. In particular, staining pattern III was associated with grade II (G2) and G3 MCTs, while staining patterns I and II were associated with G1 and G2 MCTs. Considering the 2-tier histological grading, the high grade was mainly associated with pattern III (71%) while the low grade was associated with patterns II (70%) and I (28%). A weak association between the KIT staining pattern and outcome was also observed. The results obtained suggest that c-KIT mRNA is overexpressed in canine MCT, although the fold variations were not associated with the protein localization or complementary DNA mutations. These observations suggested that the 3 events were independent. The histological grading and the KIT staining pattern have prognostic value as previously published. Staining pattern I could be especially helpful in predicting a good prognosis of G2 MCTs. Sequence mutations were not necessarily suggestive of a worse prognosis, but might be useful in choosing a chemotherapy protocol.

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A Study of Mutations in the c-kit Gene of 32 Dogs with Mastocytoma

Cited by 38 publications

References 7 publications

Gain-of-Function Mutations in the Extracellular Domain of KIT Are Common in Canine Mast Cell Tumors

Gain-of-Function Mutations in the Extracellular Domain of KIT Are Common in Canine Mast Cell Tumors

Cellular Proliferation in Canine Cutaneous Mast Cell Tumors: Associations with c-KIT and Its Role in Prognostication

c-KIT messenger RNA and protein expression and mutations in canine cutaneous mast cell tumors

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