PATH-50 - Genetic and epigenetic profiling of meningiomas to gain insights into molecular heterogeneity and risk stratification.

Background: Meningiomas are slow-growing CNS tumors, with most being benign (WHO grade 1) and having indolent behavior. Limited data on molecular profiling of meningiomas and its clinical implications have hindered the implementation of effective therapies and new treatments. Aims &

Objectives: Perform DNA methylation profiling, copy number analysis, and targeted sequencing in meningiomas. Materials &

Methods: 208 meningiomas, grade 1 (n=109), grade 2 (n=83), and grade 3 (n=16)were assessed for pTERT mutation, CDKN2A homozygous deletion, and H3K27me3 expression. Additionally, 35 diagnostically challenging meningiomas underwent DNA methylation profiling, copy number analysis, and targeted sequencing.

Results: there were 199 adult and 9 pediatric cases, (mean age 44.5 years). The tumors were located in basal (53%) ,convexity (42%),and 5% in other locations.pTERT C228T mutation was detected in 4.8% and CDKN2A deletion in 2.4% cases. Loss of H3K27me3 expression was found in a significant proportion of tumors across all three grades. Methylation profiling identified four distinct molecular subgroups: Malignant, Intermediate, Benign A, and Benign B. Intermediate, Benign A, and Benign B subgroups included both WHO grade 1 and grade 2 cases. Mutations showed a strong association with specific methylation subgroups (NF2, AKT1, SMO, TRAF7, and pTERT). Loss of chromosome 22q was observed in all subgroups. 1p/14q co-deletion was predominantly seen in the malignant and intermediate subgroups (50%). CDKN2A loss was mainly observed in the malignant subgroup (50%). The DKFZ classifier successfully classified 71% of cases with an acceptable score. Methylation profiling significantly influenced PFS in WHO grade 1 and 2 meningiomas (p=0.0051).

Conclusions: Genome-wide DNA methylation profiling reveals clinically distinct molecular subgroups and heterogeneity within the same grade of meningiomas and is particularly valuable for identifying high-risk cases and predicting prognosis in WHO grade 1 and 2 meningiomas. The pTERT mutation serves as a significant and cost-effective marker for risk stratification in meningiomas.