Identification of the Aggressive Atypical Meningioma: Histopathology, Proteomic Signatures, and Genotyping

Purpose: After a gross total resection, some atypical, WHO Grade II, meningiomas carry a favorable prognosis without further therapy. However, ∼40% follow a clinically aggressive course with recurrence, invasion, and resistance to conventional therapies. Histopathology is unable to identify these “bad acting” tumors. We aimed to identify biomarker signatures in atypical meningiomas where histopathology has fallen short.

Experimental Design: Targeted next-generation sequencing for mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K, MS-based phosphoproteomics and peptide chip array kinomics were used to explore atypical meningiomas. Ingenuity Pathway Analysis (IPA) identified atypical meningioma signatures. The selected biomarkers were evaluated in an independent cohort of 320 meningioma samples and correlated with clinical variables.

Results: The MS-based phosphoproteomics and kinomic profiling revealed unique Ser/Thr phosphorylation signatures. While mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K or histological criteria (e.g., sheeting, mitoses, brain invasion, necrosis, macronucleoli) did not identify aggressive atypical meningiomas, the unique proteomic signature was associated with decreased progression/recurrence-free survival.

Conclusion: A unique aggressive atypical meningioma signature was identified using MS-based phosphoproteomics and peptide chip array kinomics. The signature was independent of histology, subtype, WHO grade or genotype. This may provide promising biomarkers for risk stratification of histologically unidentifiable aggressive WHO grade II atypical meningiomas.