Proteomic analysis of meningiomas reveals clinically-distinct molecular patterns

Meningiomas represent one of the most common and clinically heterogeneous brain tumor types that only modestly correlate with histopathologic features. While emerging molecular profiling efforts have linked specific genomic drivers to distinct clinical patterns, the proteomic landscape of meningiomas remains largely unexplored. We utilize mass spectrometry to profile a clinically well-annotated cohort (n=69) of meningiomas stratified to span all three World Health Organization (WHO) grades and various degrees of clinical aggressiveness. In total, we quantify 3042 unique proteins and compare the patterns across different clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic (n=106 proteins, Welch’s t-test, P<0.01) and pathway-level (e.g. Notch and PI3K/AKT/mTOR) differences between convexity and skull base meningiomas. Supervised comparative analyses of different pathological grades revealed distinct patterns between benign (WHO Grade I) and atypical/malignant (WHO Grade II and III) meningiomas with classic oncogenes often enriched in higher grade lesions. Independent of WHO grade, clinically aggressive meningiomas, that rapidly recurred, also had distinctive protein patterns that converged on mRNA processing and impaired activation of the extracellular matrix naba matrisome complex. Larger sized meningiomas, and those with previous radiation exposure, also had distinct protein profiles. Collectively, we highlight distinct clinically-dependent proteomic patterns of meningiomas that may help better predict outcome and guide the development of more personalized and directed therapies.