Correlation of BRAF Variant V595E, Breed, Histological Grade and Cyclooxygenase-2 Expression in Canine Transitional Cell Carcinomas

Abstract

The presence of BRAF variant V595E, as well as an increased cyclooxygenase-2 (COX-2) expression in canine transitional cell carcinoma (TCC) are well-described in the literature. The aim of the present study was to investigate the correlation between breed (terrier versus non-terrier dogs), histological grade, COX-2 expression, and BRAF mutation in canine TCC. Therefore, transmural TCC biopsies from 65 dogs (15 terriers, 50 non-terriers) were graded histologically into low- and high-grade. Immunohistochemical evaluation of the intensity of COX-2 expression was performed using an immunoreactive score (IRS). Exon 15 of chromosome 16 was examined for the BRAF variant c.1799T>A by TaqMan® SNP assay. TCC was low-grade in 20 cases (one terrier, 19 non-terriers) and high-grade in 45 cases (14 terriers, 31 non-terriers). Contrary to humans, histological grade was not significantly correlated to the intensity of COX-2 expression. BRAF mutation was detected in 11/15 (73%) TCC of terriers and in 18/50 (36%) TCC of non-terriers. Histological grade and BRAF mutation were not correlated significantly (p = 0.2912). Terriers had a considerably higher prevalence of high-grade tumors (p < 0.0001), as well as of BRAF mutation (p ≤ 0.05) compared to non-terriers. In non-terriers, neoplasms with BRAF mutation showed a significantly higher intensity of COX-2 expression than those without BRAF mutation (p ≤ 0.05). In conclusion, in contrast to humans, testing for BRAF mutation in canine TCC is a sensitive diagnostic method especially in terriers (73%) and may be recommended as a screening test. However, evidence of BRAF mutation in canine TCC is not a predictor for the histological grade. Moreover, a positive correlation between histological grade and the intensity of COX-2 expression was not found. Further studies are necessary to clarify the clinical and prognostic relevance of the elevated intensity of COX-2 expression of TCC with BRAF mutation detected in non-terriers.

Aberrant expression of the COX2/PGE2 axis is induced by activation of the RAF/MEK/ERK pathway in BRAFV595E canine urothelial carcinoma

“…From this study, since BRAF mutation was associated with pERK IHS score and pERK IHS score was clearly associated with COX2 expression, we believe that BRAF mutation would contribute to the overexpression of COX2 in cUC although the direct causal relationship of them should be further examined. In a recent study, the association between BRAF mutation and COX2 expression was suggested in cUC tissues in specific dog breeds 48 .…”

Aberrant expression of the COX2/PGE2 axis is induced by activation of the RAF/MEK/ERK pathway in BRAFV595E canine urothelial carcinoma

“…In the histological analysis, BRAF mutant cUC cells tended to show higher expression of COX2. In a recent study, the association between BRAF mutation and COX2 expression was only observed in cUC tissues of specific dog breeds 40 . Further, in our in vitro study, one of the BRAF mutant cUC cell lines did not overexpress COX2 and…”

Comparative Cancer Cell Signaling in Muscle-Invasive Urothelial Carcinoma of the Bladder in Dogs and Humans

“…Recently, a commercially available diagnostic test was developed to non-invasively detect the BRAF V595E mutation in cells shed into the urine using droplet PCR. However, this mutation is only present in the urine of ~65-80% of dogs with MIUC [150,151], prostate cancer [151] and other types of canine cancers [145,152] making it non-specific for UC. In addition, the presence of the BRAF V595E mutation might be breed specific.…”

“…In addition, the presence of the BRAF V595E mutation might be breed specific. A study examining MIUC tissues from dogs of different breeds found that the presence of the BRAF V595E mutation is more frequent in terriers (n = 15, 73%) compared to non-terriers with MIUC (n = 50, 36%) (p < 0.05) [152].…”