Expression frequency of c-kit isoforms and its prognostic potential in canine mammary tumours

摘要

KIT is a tyrosine kinase receptor involved in carcinogenesis. Two alternatively spliced transcripts, differed from presence of four amino acids (GNSK) at exon 9 of c-kit, were identified in various human tumours and canine hemangiosarcoma (HSA). The biological function and clinical implications of these isoforms have not yet been elucidated in canine tumours. The current study aimed to validate the expression profile and ultimately to evaluate the correlation of c-kit isoform levels with clinicopathological factors of canine mammary tumours (CMTs). In total, the expression profiles of c-kit isoforms in 196 samples obtained from normal mammary glands (NMGs) of healthy controls and dogs with CMTs, benign and malignant CMTs, and HSAs were determined by polymerase chain reaction (PCR) and quantified via real-time PCR. Overall, the expression levels of the two isoforms were equivalent in NMGs, whereas the GNSK(-)/GNSK(+) ratio sharply increased to 7.44- and 8.33-fold, indicating abundant GNSK(-) isoforms in benign and malignant CMTs, respectively. However, a significant decrease in GNSK(-) expression was detected in dogs with high-grade malignant CMTs (mCMTs) and with metastatic CMTs compared with expression in those with a lower grade and non-metastatic CMTs. In addition, the median survival time was shorter in mCMT canines with a lower GNSK(-)/GNSK(+) ratio than that in mCMT canines with a higher ratio (899 days vs 1534 days). In conclusion, two c-kit isoforms are ubiquitously expressed with great variability in HSAs and CMTs with both benign and malignant status. The GNSK(-)/GNSK(+) ratio could serve as a prognostic indicator for dogs with mCMTs.