Mutational analysis of c-kit and PDGFR in canine gastrointestinal stromal tumours (GISTs)

Introduction: even though relatively rare, GISTs are the most common mesenchymal tumour of the canine GI tract and are diagnosed by the immunohistochemical expression of the receptor tyrosine kinase (RTK) KIT. Activating mutations of the proto-oncogenes c-KIT and PDGFRA drive GIST oncogenesis and are used for predicting response to RTK-inhibitors in human oncology. Since the frequency and significance of these mutations are known incompletely, the aim of this study was to ascertain the type and frequency of KIT and PDGFRA mutations in a series of canine GISTs. Materials and methods: the mutational status of c-KIT (exons 8, 9 and11) and PDGFRA (exons 12 and 18) genes was explored by DHPLC, genescanning and direct sequencing using RT-PCR in a series of 17 canine GISTs confirmed by CD117, PDGFRA, sm-actin and desmin immunohistochemistry. Results: c-KIT mutations were detected in 8/17 cases (47%) and always involved exon 11 (deletion of 6-46 pb), whereas exons 9 and 13 were wild type in all cases. PDGFRA gene mutation was identified only in one case in the exon 18 (c.2522 G>A, SNP activating mutation). Even if follow-up was not available for all cases, liver metastases were documented in 5 cases, and all these cases displayed mutation in c-KIT exon-11. Conclusions: c-KIT exon-11 mutations occur frequently in canine GISTs and seem associated to aggressive behavior. PDGFRA activating mutation are less frequent and never reported before in canine GISTs. Further studies are warranted to demonstrate the prognostic and predictive role of KIT or PDGFRA mutations in canine GISTs cases, liver metastases were documented in 5 cases, and all these cases displayed mutation in c-KIT exon-11.