Chromosomal gain and mutations of platelet-derived growth factor receptor-α gene in canine high-grade oligodendroglioma.

Abstract

Canine high-grade oligodendrogliomas (HGOGs) exhibit a high expression of platelet-derived growth factor receptor-α (PDGFRA). We examined PDGFRA mutations and gain of PDGFRA and their association with the PDGFRA expression and proliferation of tumor cells in canine HGOG cases and cell lines. Polymerase chain reaction and sequence analysis revealed expected pathogenic mutations in PDGFRA exons 7 and 8 in 16/34 (47%) cases. However, these mutations were not associated with PDGFRA expression, as examined by mRNA in situ hybridization (ISH) and immunohistochemistry, or proliferation activity, as examined by the Ki-67 labeling index (LI). Chromosomal ISH performed in 16 cases revealed PDGFRA and endoplasmic reticulum membrane protein complex subunit 2 (EMC2) gains in 15 cases (94%). PDGFRA gain was moderately correlated with PDGFRA mRNA expression (ρ = 0.54, P = .04) and were moderately correlated with PDGFRA H-score, which is the score based on immunolabeling intensity (ρ = 0.44, P = .09). However, PDGFRA gain was not correlated with the Ki-67 LI (ρ = 0.23, P = .38). The canine HGOG cell line with PDGFRA gain showed higher PDGFRA mRNA expression (P < .01), H-score (P < .01), and Ki-67 LI (P < .01) than the cell line without PDGFRA gain in vitro. The gain of PDGFRA and EMC2 suggests polysomy of canine chromosome 13, where both genes are located. The in vitro analysis results suggested that chromosome 13 polysomy is associated with increased PDGFRA expression and cell proliferation in canine HGOG. Chromosome 13 polysomy may be involved in canine gliomagenesis by increasing PDGFRA expression and inducing tumor cell proliferation.