2025 Proffered Presentations
S242: GENETIC ANALYSIS POINTS TO A DISTINCT TRANSCRIPTOMIC IDENTITY FOR GRADE II MENINGIOMAS
Joshua A Reynolds, MS1; Isabella L Pecorari, BS1; Abigail Funari, MD2; Kith Pradhan, PhD3; Amit Verma, MD4; Emad N Eskandar, MD1; Vijay Agarwal, MD1; 1Department of Neurological Surgery, Montefiore Medical Center-Albert Einstein College of Medicine; 2Department of Neurosurgery, SUNY Upstate Medical University; 3Department of Epidemiology and Population Health, Albert Einstein College of Medicine; 4Department of Hematology-Oncology, Albert Einstein College of Medicine
Introduction: While WHO Grade I and Grade III meningiomas are clinically and molecularly well-described, Grade II tumors, comprising 20% of all meningiomas, are less understood. This class exhibits features of a distinct oncologic entity, such as varied treatment responsivity, natural history, and increased malignant potential. However, incomplete characterization of Grade II meningiomas limits the ability to tailor therapy to this intermediate grade. Therefore, the goal of this study was to determine if genetic features distinguish Grade II from Grade I tumors.
Methods: Through a retrospective chart review, 95 patients were identified who underwent surgical resection of intracranial meningiomas at our institution between 2008 and 2018. Following exclusion criteria application, formalin-preserved samples, which were collected intra-operatively, from nine WHO Grade I and ten WHO Grade II meningiomas underwent bulk mRNA sequencing. Notably, these primary analyses were performed in two separate experiments, but transcriptomic results were normalized to internal control genes to address the resulting batch effects. Differential expression analysis yielded fold-change (Grade II over Grade I) and multiple-test-corrected significance (q-value < 0.05) values for each of the 45,000 genes assessed. Gene-set enrichment analysis (GSEA), with each gene weighted by its differential expression, was then performed using the Molecular Signatures Database (MSiG) and each of its nine human reference gene-sets. Normalized enrichment scores (positive equals enriched in Grade II over Grade I) and q-values were produced for each of the reference ontology terms.
Results: 28,869 genes had sufficient expression in all samples for further analysis. Compared to Grade I, Grade II meningiomas displayed an increased average expression of 3,512 genes and decreased average expression of 5,615 genes (Figure 1A). To better understand the biological relevance of these transcriptomic differences, GSEA uncovered 11,433 unique ontology terms significantly altered in Grade II tumors (Figure 1B). Interestingly, 10,057 of these pathways were enriched in Grade II (Normalized Enrichment Score > 1.23; q-value < 0.05). In terms of degree of enrichment, immunologic functions and cell-type determinants represented 65% and 31% of the top 100 terms, respectively. We next focused on the Hallmark library of MSiG, which provides a more general picture of pathway enrichment (Figure 2). Among the top 10 enriched pathways, several metabolic functions, including oxidative phosphorylation and glycolysis, were upregulated in Grade II meningiomas. Similarly, there was a significant increase in the cellular stress pathways involving p53, hypoxia responses, reactive oxygen species production, and the epithelial-mesenchymal transition. Immunologic regulation, including MTORC1 signaling and TNF-alpha signaling via NFKB, was also meaningfully elevated.
Conclusions: Through bulk transcriptomic analysis, the present study detected functionally relevant alterations in Grade II meningiomas which distinguish this class from Grade I tumors. Specifically, enhanced expression of metabolic, cellular stress, and immunologic pathways potentially underly the higher clinical severity of Grade II tumors. Future studies will seek to further uncover the specific mediators of these hallmarks and ascertain their mechanistic impact and potential role in treating Grade II meningiomas.
