Gene Expression Signatures Identify Biologically Homogenous Subgroups of Grade 2 Meningiomas

Abstract

Introduction: Meningiomas are the most common brain tumor, with prevalence of approximately 3%. Histological grading has a major role in determining treatment choice and predicting outcome. While indolent grade 1 and aggressive grade 3 meningiomas exhibit relatively homogeneous clinical behavior, grade 2 meningiomas are far more heterogeneous, making outcome prediction challenging. We hypothesized two subgroups of grade 2 meningiomas which biologically resemble either World Health Organization (WHO) grade 1 or WHO grade 3. Our aim was to establish gene expression signatures that separate grade 2 meningiomas into two homogeneous subgroups: a more indolent subtype genetically resembling grade 1 and a more aggressive subtype resembling grade 3. Methods: We carried out an observational meta-analysis on 212 meningiomas from six distinct studies retrieved from the open-access platform Gene Expression Omnibus. Microarray data was analyzed with systems-level gene co-expression network analysis. Fuzzy C-means clustering was employed to reclassify 34 of the 46 grade 2 meningiomas (74%) into a benign “grade 1-like” (13/46), and malignant “grade 3-like” (21/46) subgroup based on transcriptomic profiles. We verified shared biology between matching subgroups based on meta-gene expression and recurrence rates. These results were validated further using an independent RNA-seq dataset with 160 meningiomas, with similar results. Results: Recurrence rates of “grade 1-like” and “grade 3- like” tumors were 0 and 75%, respectively, statistically similar to recurrence rates of grade 1 (17%) and 3 (85%). We also found overlapping biological processes of new subgroups with their adjacent grades 1 and 3. Conclusion: These results underpin molecular signatures as complements to histological grading systems. They may help reshape prediction, follow-up planning, treatment decisions and recruitment protocols for future and ongoing clinical trials.