481P - Integrating GWAS and transcriptomics prioritizes drug targets for meningioma

Background

Meningiomas, common brain tumors with an annual global incidence of about 8.83 per 100,000, are mostly benign and surgically removable. High-grade meningiomas, however, show poor outcomes and high recurrence. The research aims to understand their genetic and cellular nature to improve treatment, using methods like Mendelian randomization and single-cell transcriptomics.

Methods

Our study integrated eQTL and GWAS data, utilizing transcriptomic datasets including GSE77259 and GSE183655, to explore gene expression in meningiomas. We applied summary-data-based Mendelian Randomization (SMR) and colocalization analysis to identify genetic associations and potential drug targets. Bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) analyses provided insights into the gene expression and cellular heterogeneity in meningiomas. Techniques like single-cell flux estimation analysis (scFEA) and CytoTalk helped understand cellular metabolism and signaling pathways. Additionally, molecular docking was used to predict potential therapeutic compounds for meningioma treatment.

Results

Our analysis identified four genes significantly associated with meningiomas through SMR, COLOC, and MR, indicating a causal relationship. Bulk RNA validation showed XBP1, TRPC6, and TTC28 upregulated in meningioma tissues. Single-cell RNA sequencing confirmed the high expression of these genes in specific cell types within meningioma samples. Analysis revealed the three genes significantly coexpress in tissue stem cells, with metabolic pathway involvement identified. Cell-cell interaction studies highlighted the critical role of tissue stem cells in communication networks, particularly in CD99, COLLAGEN, and FN1 signaling pathways. Molecular docking experiments demonstrated the potential of Dexamethasone and Levonorgestrel in modulating the expression of these meningioma-related genes, suggesting their therapeutic relevance.

Conclusions

The discovery of TRPC6, XBP1, and TTC28 as meningioma therapy targets advances our disease understanding, prompting further research into their roles and therapeutic validation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Cerebrovascular Disease Youth Innovation Fund of China International Medical Foundation, and Chinese Stroke Association Cerebrovascular Disease Innovation Medical Research Foundation.

Disclosure

All authors have declared no conflicts of interest.