EGFR, HER-2 and KRAS in canine gastric epithelial tumors: a potential human model?

Abstract

Epidermal growth factor receptor (EGFR or HER-1) and its analog c-erbB-2 (HER-2) are protein tyrosine kinases correlated with prognosis and response to therapy in a variety of human cancers. KRAS mediates the transduction of signals between EGFR and the nucleus, and its mutation has been identified as a predictor of resistance to anti-EGFR drugs. In human oncology, the importance of the EGFR/HER-2/KRAS signalling pathway in gastric cancer is well established, and HER-2 testing is required before initiating therapy. Conversely, this pathway has never been investigated in canine gastric tumours. A total of 19 canine gastric epithelial neoplasms (5 adenomas and 14 carcinomas) were retrospectively evaluated for EGFR/HER-2 immunohistochemical expression and KRAS mutational status. Five (35.7%) carcinomas were classified as intestinal-type and 9 (64.3%) as diffuse-type. EGFR was overexpressed (≥ 1+) in 8 (42.1%) cases and HER-2 (3+) in 11 (57.9%) cases, regardless of tumour location or biological behaviour. The percentage of EGFR-positive tumours was significantly higher in the intestinal-type (80%) than in the diffuse-type (11.1%, p = 0.023). KRAS gene was wild type in 18 cases, whereas one mucinous carcinoma harboured a point mutation at codon 12 (G12R). EGFR and HER-2 may be promising prognostic and therapeutic targets in canine gastric epithelial neoplasms. The potential presence of KRAS mutation should be taken into account as a possible mechanism of drug resistance. Further studies are necessary to evaluate the role of dog as a model for human gastric cancer.

Figure 1. EGFR and HER-2 immunohistochemistry of canine samples.

(A). Dog, stomach. Signet ring cell carcinoma (case No. 15). EGFR immunohistochemistry. Faint and partial membrane labelling of the neoplastic cells (1+). Haematoxylin counterstain. 200x. (B) Dog, stomach. Papillary adenoma (case No. 2). EGFR immunohistochemistry. Strong and complete membrane labeling of the neoplastic cells (3+). Haematoxylin counterstain. 100x. (C) Dog, stomach. Tubulopapillary adenoma (case No. 4). HER-2 immunohistochemistry. Moderate basolateral membrane labeling of the neoplastic cells (2+). Haematoxylin counterstain. 200x. (D) Dog, stomach. In situ tubulopapillary carcinoma (case No. 6). HER-2 immunohistochemistry. Strong and complete membrane labeling of the neoplastic cells (3+). Haematoxylin counterstain. 200x. (E) Dog, stomach, fundus. EGFR immunohistochemistry. Negative labeling of the mucosal epithelium. Faint granular cytoplasmic positivity of the parietal cells. Haematoxylin counterstain. 200x. (F) Dog, stomach, pyloric antrum. HER-2 immunohistochemistry. Scattered foci of faint basolateral positivity. Haematoxylin counterstain. 200x.

Figure 2. KRAS analysis.

Mutation analysis performed by direct sequencing on wild type (A) and mutated (B) samples. Arrows indicate the point mutation.