2025 Proffered Presentations
S237: IMMUNOLOGIC HALLMARKS DISTINGUISH THE TRANSCRIPTOMES OF GRADE I AND 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: WHO Grade II meningiomas potentially represent a distinct oncologic entity from Grade I and Grade III tumors. Nonetheless, researchers have only just begun to appreciate the biologic and genomic features specific to tumors of this intermediate grade. Previous work from our group found that Grade II meningiomas disproportionately express genes in the pathways regulating the extracellular matrix, cell stress response, and immune system signaling. The influence of the immune system has previously been shown to play a role in meningioma progression. Therefore, the goal of this study was to assess if Grade II meningiomas display enrichment of immunologic pathways and mediators relative to Grade I tumors.
Methods: Formalin-preserved tumor samples from nine WHO Grade I and ten WHO Grade II meningiomas underwent bulk mRNA sequencing. These were drawn from a cohort of 95 patients that had surgical resection of intracranial meningioma at our institution between 2008 and 2018. In these primary analyses, transcriptomic results were normalized to internal control genes to address the resulting batch effects of the separate experiments. Gene-set enrichment analysis of the 45,000 quantified genes was performed using the Molecular Signatures Database (MSiG) and its Hallmark library. Normalized enrichment scores (positive equals enriched in Grade II over Grade I) and multiple-test-corrected significance (q-value<0.05) were produced for each of the immunology-relevant ontology terms. Next, the specific genes that contributed most frequently to the enrichment of these immunologic pathways were identified, and the mean expression within the tumor grades for the top five genes was compared.
Results: The immunologic pathways most enriched in Grade II meningiomas largely related to inflammatory signaling (Figure 1). The intracellular mediators mTOR complex 1 (MTORC1) and NF-kappaB (NFKB), which both regulate the cell-cycle and lymphocyte behavior, were the two most enriched pathways. Signaling through cytokines, such as TNF-alpha, interferons alpha and gamma, interleukins 2 and 6, and TGF-beta, comprised many of the top enriched pathways. Among the 506 unique genes contributing to at least one of these ten immunologic pathways, a core group of five genes played a role in four or more of the pathways (Figure 2). C-C motif chemokine ligand-5 (CCL5, RANTES; q=0.020), cyclin dependent kinase inhibitor-1A (CDKN1A; q=0.005), colony stimulating factor-1 (CSF1, M-CSF; q=0.009), interferon gamma receptor-2 (IFNGR2; q=0.008), and interferon regulatory factor-7 (IRF7; q=0.001) each displayed a higher level of expression in Grade II compared to Grade I meningiomas (Figure 2A-E).
Conclusions: The present study identified inflammatory pathways and mediators that appear to be upregulated in Grade II compared to Grade I meningiomas. In particular, TNF-alpha, interferon-gamma, and interleukin-6 signaling pathways have well-established neuroinflammatory effects which may contribute to the more severe clinical features of Grade II tumors. Subsequent gene-level assessment emphasized specific moderators of these pathways, including CCL5, CSF1, and IRF7. Future studies will assess the mechanistic role of these mediators in the hope of better understanding and eventually targeting the pathogenic changes unique to Grade II meningiomas.
