Anti-MGMT monoclonal antibody, clone NU3.2

INTRODUCTION. The clinical and molecular correlates of glioblastomas (GBMs) contacting the subventricular zone (SVZ+ GBM) are unknown. This work aimed to reveal any such correlates that may help explain their increased GBM malignancy. EVIDENCE ACQUISITION. A meta-analysis was, therefore, conducted to assess whether tumor's MGMT promoter methylation status, isocitrate dehydrogenase (IDH) mutation status, volume, and extent of resection as well as patients' age at diagnosis and preoperative Karnofsky performance status score (KPS) correlate with SVZ contact by GBM. In addition, available imaging of GBM patients in The Cancer Imaging Archive was assessed for SVZ contact and their corresponding clinical and molecular variables were obtained through The Cancer Genome Atlas (TCGA) database. EVIDENCE SYNTHESIS. Twenty-one studies were identified through PubMed and EMBASE database search. This review included 257 patients identified from the TCIA/TCGA database. MGMT promoter methylation status (summary odds ratio [OD], 1.18 [0.84-1.66], P=0.34), IDH mutation status (OD: 0.63 [0.20-1.99], P=0.43), and patients' age of diagnosis (summary mean difference, MD, 0.10 years [-1.85, 2.05], P=0.92) did not associated with SVZ contact of the GBM. However, SVZ+ GBMs were significantly larger than SVZ- GBMs (MD: 17.3 cm(3) [8.70-25.8], P<0.0001). SVZ+ GBM patients had lower KPS scores (MD: -3.33 [-5.31-(-1.35)], P=0.001) and were half as likely to receive a gross total resection (OD: 0.50 [0.40-0.64], P<0.00001). CONCLUSIONS. Additional, large studies that rigorously control for all the known clinical and molecular prognosticators, especially extent of resection and preoperative KPS scores, are needed to evaluate whether SVZ contact by GBM independently influences survival.

In search of novel genes associated with glioma pathogenesis, we have previously shown frequent deletions of the KIAA1797/FOCAD gene in malignant gliomas, and a tumor suppressor function of the encoded focadhesin impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examined an association of reduced FOCAD gene copy number with overall survival of patients with astrocytic gliomas, and addressed the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II-IV. Multivariate analysis considering age at diagnosis as well as IDH mutation, MGMT promoter methylation, and CDKN2A/B homozygous deletion status confirmed reduced FOCAD gene copy number as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, tubulin beta-6 and other tubulin family members were identified as novel focadhesin-interacting partners. Tubulins and focadhesin co-localized to centrosomes where focadhesin was enriched in proximity to centrioles. Focadhesin was recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduced microtubule assembly rates, possibly explaining the focadhesin-dependent decrease in cell migration. During the cell cycle, focadhesin levels peaked in G2/M phase and influenced time-dependent G2/M progression potentially via polo like kinase 1 phosphorylation, providing a possible explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression.