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

Abstract

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.

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

“…Compared to previously published studies, the mutational status of our case series, including both primary and secondary metastatic tumors, showed a similar proportion of c‐kit mutations 23. Two already known SNPs were found in exon 8 and 113, 30; furthermore, 3 novel mutations (1 in exon 8 and 2 in exon 11), with unknown clinical relevance, were found.…”

“…Another question, still matter of debate, is whether activating c‐kit mutations might be related to a poor prognosis in canine MCTs 23, 37. Based on our results, dogs with c‐kit mutations had a shorter survival time when compared with dogs with WT MCTs.…”

Comparação de duas classificações histopatológicas com o padrão de imuno-marcação para KIT, a avaliação da proliferação celular e com a presença de mutações no c-KIT de mastocitomas cutâneos caninos

“…O padrão KIT é considerado um forte fator prognóstico para os mastocitomas caninos, especialmente no que diz respeito à associação entre o padrão citoplasmático, o aumento da proliferação celular, o grau histopatológico (Zemke et al 2002, Kiupel et al 2005, Webster et al 2006a, Giantin et al 2012) e a um comportamento mais agressivo (Patruno et al 2014). O presente estudo demonstrou forte associação entre o padrão KIT e a classificação histológica.…”

“…A classificação de alto grau é aquela que tem o pior prognóstico (Kiupel et al 2011), por isso, a maior frequência de mutações nos tumores de alto grau é esperada. Giantin et al (2012) descreveram a presença de mutação em todos os graus histopatológicos, mas a porcentagem de tumores de baixo grau com mutação foi maior do que os tumores de alto grau.…”

“…O mesmo foi verificado por Webster et al (2006a), que sugerem que a mutação em outros locais ou outros fatores podem estar relacionados à alteração da localização membranosa do KIT. Tanto a presença de mutação ou a localização aberrante do KIT estão associados a prognósticos piores (Webster et al 2007), mas mesmo tumores sem mutação podem proliferar e ter comportamento maligno (Giantin et al 2012). Segundo Webster et al (2006a), a localização aberrante do KIT é mais importante na patogênese do tumor do que a superexpressão do c-KIT.…”