MET immunolabelling is a useful predictive tool for MET gene amplification in glioblastoma

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Glioblastoma (GBM) is the most common malignant brain tumour in adults. Despite aggressive therapy based on a combination of surgery, radiotherapy and chemotherapy, the prognosis of GBM remains poor, with a median overall survival of less than 15 months 1. GBM are a genetically heterogeneous group of tumours. Alterations of TP53, RB and of tyrosine kinase receptor pathways are among the most frequent anomalies in GBM 2. The Cancer Genome Atlas (TCGA) identified at least four distinct molecular subgroups of GBM 3. Genetic or gene expression alterations of EGFR, NF1 and PDGFRA/IDH1 define classical, mesenchymal and proneural subtypes respectively. The neural subtype is typified by the expression of neuronal markers. Some novel genetic alterations, such as TERT or ATRX mutations have recently been identified 4. Their detection may be used to define glioma subgroups. Furthermore, genetic profiling of GBM is of increasing interest because the discovery of targetable abnormalities raises the prospect of personalized treatment.
Both the tyrosine kinase receptor mesenchymal–epithelial transition (MET) and its ligand, the hepatocyte growth factor (HGF) are involved in cell proliferation, survival, migration, invasion and angiogenesis. Activation of MET/HGF signalling is involved in the pathogenesis of numerous cancers including GBM 6. Four per cent of GBM harbour an amplification of MET2 resulting in overexpression and constitutive activation of the kinase protein. Crizotinib (PF‐02341066) is a tyrosine kinase inhibitor which targets altered ALK, ROS1 or MET tyrosine kinase receptors 9. Its prescription is currently restricted to adult patients with lung cancer showing translocation of ALK gene 11. Promising results have been reported in one case of MET‐amplified GBM treated by crizotinib 12. The controlled clinical phase II trial ‘AcSé‐Crizotinib’ (EudraCT 2013‐000885‐13) actively supported by the French National Institute of Cancer (INCa) was launched in France in July 2013. This trial permits patient access to crizotinib for nonpulmonary cancer resistant to standard treatment when the tumours show at least one of the targets for this agent. According to INCa recommendations, MET alterations in tumours should be prescreened by immunohistochemistry. Patients are eligible for crizotinib treatment when more than 50% of tumour cells strongly express MET protein in the presence of MET gene alteration. GBM with MET amplification have been included in this trial since October 2014. However, we believe that the criteria defining immunohistochemical positivity for MET expression should be defined for the specific context of GBM. To the best of our knowledge, there are no currently available data describing the correlation of protein MET immunolabelling to MET gene status in GBM. The aim of this study was to define the immunohistochemical pattern of MET expression associated with MET amplification in GBM, in order to provide a useful screening tool.
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