MYBL2: a novel aggressive biomarker in IDH-mutant Astrocytoma

Abstract

Abstract Purpose:Astrocytoma, IDH-mutant includes CNS WHO grades 2 (A2), 3(A3) and 4(A4). A3 patients have a heterogenous clinical outcome that cannot be fully explained with existing molecular biomarkers. In our previous study we found MYBL2 mRNA to be upregulated in A3 and associated with poor patient outcome. In this study, we aimed to understand the role of MYBL2 in the pathobiology of A3 and clinical course of these patients. Methods:Protein expression of MYBL2 was investigated on a cohort of A3 and controls using immunohistochemistry (IHC). Its expression was evaluated in paired primary and recurrent samples of A3 and in A2 and A4 tumors. We also assessed p53 immunoreactivity, an important modulator of MYBL2. Functional role of MYBL2 was studied in vitro in three malignant astrocytoma cell-lines [SW1088 and SW783-Secondary cell lines and A3 Primary cell line] using a siRNA knock down approach. Results:MYBL2 median labelling index (LI) was 15% (0-50%) in A3. Higher MYBL2-LI was associated with shorter PFS (P=0.044) and OS (P=0.017). MYBL2 LI was higher in recurrent tumors compared to primary and in A3 and A4, compared to A2 (P<0.05). p53 LI correlated positively with MYBL2 LI (p=0.026). MYBL2 knockdown was associated with reduced tumor cell proliferation, invasion, and migration. Conclusion:Our study identified MYBL2 as a novel aggressive biomarker associated with poor prognosis in A3 and with tumor progression. MYBL2 facilitates tumor cell proliferation, migration, and invasion of malignant astrocytoma cells in vitro. Taken together, MYBL2 can be considered as a potentially useful prognostic marker for A3 tumors.