Isocitrate dehydrogenase 1 R132H: epidermal growth factor receptor and Ki-67 expression in canine gliomas
AuthorFraser, Anne Rosemary
AffiliationVeterinary Clinical Sciences
Document TypeMasters Research thesis
Access StatusThis item is embargoed and will be available on 2021-07-15.
© 2019 Anne Rosemary Fraser
The diagnosis, histological classification and grading of canine gliomas can be challenging, particularly in the antemortem. In humans, it is essential to accurately diagnose gliomas as the treatment and prognosis vary between tumour histologic type and grade. Numerous biomarkers have been investigated to aid in the diagnosis and classification of human gliomas, including epidermal growth factor receptor (EGFR), Ki-67 and a point mutation in the isocitrate dehydrogenase 1 gene at codon 132 (IDH1 R132H). Only limited studies looking at these biomarkers have been performed in dogs, from which clear conclusion cannot be drawn. The prognosis for canine glial tumours is considered guarded to poor, with the current treatment options having limited success. Consequently, there is a lack of gold standard treatment for canine glioma. In humans, gliomas are being investigated at a molecular level to identify therapeutic targets and to improve responsiveness to treatment. Numerous molecular targets have been identified including EGFR and IDH1 R132H. Canine gliomas share many morphologic, histologic and immunohistochemical characteristics with human gliomas, suggesting a translational approach to the classification, treatment and prognostication of canine gliomas may be possible. The objectives of this research were: (1) to describe the signalment, presenting clinical signs, diagnostic findings, treatment and survival time of a series of dogs with glial tumours, (2) to investigate the series of canine gliomas for the IDH1 R132H mutation, and for EGFR and Ki-67 expression, utilising immunohistochemistry and (3) to determine if immunoreactivity is associated with tumour histologic type and grade. The clinical data of thirty-one dogs with histologically confirmed glial tumours was reviewed retrospectively. The formalin-fixed paraffin-embedded tumour specimens were evaluated for IDH1 R132H, pan-IDH1 (IDH1 wild-type and mutated IDH1), EGFR and Ki-67 expression. IDH1 R132H and pan-IDH1 expression were recorded as positive or negative. EGFR immunoreactivity was evaluated using a semi-quantitative score, and Ki-67 expression was expressed as the Ki-67 labelling index (LI). Patient signalment, clinical presenting signs and diagnostic investigation findings were similar to previous reports. The IDH1 R132H point mutation was not identified in any (0%) of the canine glial tumours, while all 31 (100%) tumours were positive for pan-IDH1 expression. EGFR expression was identified in 16/31 (51.6%) tumours and expression was significantly greater in high grade gliomas when compared to low grade tumours (P = 0.04). Furthermore, EGFR expression was significantly greater in gliomatosis cerebri when compared to oligodendroglioma (P = 0.002), astrocytoma (P = 0.01), and oligoastrocytoma (P = 0.04). Ki-67 expression was identified in 28/31 (90.3%) gliomas, and the Ki-67 LI was significantly higher in high grade tumours (P = 0.02). A significant moderate correlation between the Ki-67 LI and EGFR immunoreactivity (r = 0.47, P = 0.007) was identified. The IDH1 R132H point mutation was not identified in this series of canine gliomas, and may not be an appropriate biomarker to aid in the classification and treatment of these tumours. EGFR, however, may be a suitable therapeutic target, particularly for gliomatosis cerebri. The Ki-67 LI may aid in the development of a grading scheme for canine gliomas.
KeywordsIsocitrate dehydrogenase 1 R132H; epidermal growth factor receptor; Ki-67; glioma; oligodendroglioma; astrocytoma; oligoastrocytoma; gliomatosis cerebri; canine; immunohistochemistry
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