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S148: RADIATION-INDUCED TRANSCRIPTOMIC REPROGRAMMING IN HIGH-GRADE MENINGIOMAS RESTORES ANTIGEN PRESENTATION AND SUPPRESSES ONCOGENIC AND SURVIVAL PATHWAYS
Ishav Y Shukla, BS; Jeffrey I Traylor, MD; Matthew Z Sun, MD; Aaron Plitt, MD; UT Southwestern Medical Center

Introduction: Radiation therapy (RT) is commonly used in the management of high-grade meningiomas, particularly for recurrent or residual disease. The molecular consequences of RT on tumor biology remain incompletely defined, limiting rational development of adjuvant strategies. We analyzed open-source RNA sequencing data from WHO grade 3 meningiomas with and without prior radiation therapy, alongside normal human dura controls to characterize transcriptional changes associated with radiation exposure.

Methods: RNA-seq data were obtained from three separate studies available in the NCBI Gene Expression Omnibus (GEO) database: cadaveric dura, radiation-naïve grade 3 meningiomas, and grade 3 meningiomas post-RT. Differential expression was assessed using DESeq2, with log fold change (LFC) and false discovery rate (FDR, Benjamini–Hochberg adjusted p) reported. Genes were categorized by biological function, including antigen presentation, oncogenic signaling, stress and survival pathways, receptor expression, and interferon-stimulated genes.

Results: Post-RT tumors demonstrated significant increases in antigen presentation pathways, including TAP1 (LFC +5.28, p < 0.001), HLA-DQA1 (LFC +5.49, p < 0.001), HLA-DQA2 (LFC +7.34, p < 0.001), and HLA-DQB1 (LFC +5.22, p < 0.001), all of which remained significant after Bonferroni correction. Conversely, RAS/MAPK signaling was suppressed in post-RT tumors, with KRAS (LFC −3.58, p < 0.001) and NRAS (LFC −1.46, p < 0.001) both reduced; KRAS remained significant after Bonferroni correction. Genes associated with replication stress and apoptosis resistance were also downregulated, including PCNA (LFC −1.80, p < 0.001), BCL2 (LFC −2.28, p < 0.001), and GADD45 family members. Receptor profiling revealed SSTR2 expression was among the most significantly decreased transcripts (LFC −4.71, p < 0.001, Bonferroni significant). Several interferon-stimulated genes, including IRF1 (LFC −1.41, p = 0.001), ISG15 (LFC −2.05, p = 0.004), RSAD2 (LFC −1.64, p = 0.011), IFI6 (LFC −1.58, p = 0.020), and BST2 (LFC −1.60, p = 0.030), were also reduced in post-RT tumors, although none remained significant after Bonferroni correction. Notably, antigen presentation genes were reduced in non-radiated tumors compared to dura but restored in post-RT tumors, KRAS was upregulated in non-radiated tumors compared to dura but downregulated after radiation, and SSTR2 was highly enriched in non-radiated tumors relative to dura but decreased following radiation.

Conclusion: RNA-seq profiling reveals that radiation may reprogram grade 3 meningiomas by restoring antigen presentation, suppressing oncogenic MAPK signaling, and attenuating replication stress, survival pathways, and SSTR2 overexpression, while also dampening interferon-driven transcriptional activity. These findings suggest that radiation mitigates several malignant transcriptional changes characteristic of WHO grade 3 meningiomas. This reprogramming may have therapeutic implications: restoration of antigen presentation could enhance immune visibility and suppression of MAPK and BCL2 pathways reduces reliance on oncogenic survival signaling.

 

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