Abstract 5585: Genetic variants of IDH and EGFR as diagnostic and prognostic biomarkers in glioblastoma multiforme: A case-control study in the Jordanian Arab population
Authors: Al-Bzour Ayah N. , Al-Khatib Sohaib M. , Almajali Mohammad N. , Jarrad Tariq A. 
Published: March 2024

Abstract
Background: Glioblastoma multiforme (GBM) represents a highly aggressive primary brain tumor with poor prognosis. Mutation in the Isocitrate dehydrogenase (IDH1) gene and epidermal growth factor (EGFR) amplification are key diagnostic markers for GBM. However, the prognostic role of genetic variants of these genes remains unclear. Therefore, we aimed to investigate the association between specific single nucleotide polymorphisms (SNPs) for IDH and EGFR genes, and their impact on the risk and prognosis of GBM patients within the Jordanian Arab population.
Methods: We carried out a case-control study involving 63 GBM patients and 226 healthy controls at King Abdullah University Hospital in Jordan. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tissue for GBM patients and blood samples for controls. IDH1 (rs121913500C&gt;T), IDH2 (rs11540478G&gt;A), EGFR (rs231677G&gt;A), and EGFR (rs1468727C&gt;T) SNPs were genotyped and analyzed using the Sequenom iPLEX assay sequencing technique. Overall survival (OS) was analyzed between SNPs using the univariable Cox proportional hazard model. The Cancer Genome Atlas (TCGA-GBM) cohort of 585 patients were analyzed for IDH1, IDH2, and EGFR alterations with OS, disease-free survival (DFS), and progression-free survival (PFS). Single-cell RNA analysis was performed on the following scRNA datasets from the Gene Expression Omnibus (GEO): GSE163108 (n=25,013 cells), and GSE102130 (n=3,321 cells) .
Results: Our study revealed a significant difference in genotype frequency between GBM cases and controls for IDH1 rs121913500C&gt;T, and EGFR rs1468727C&gt;T SNPs. Univariable Cox model showed that the G/G genotype of rs231677G&gt;A (EGFR) SNP was associated with better OS in the codominant model (HR: 0.24, 95% CI: 0.08-0.73, p-value=0.012), and rs11540478G&gt;A (IDH2) SNP (HR: 0.02, 95% CI: 0.0-0.29, p-value=0.005) showing significantly better prognosis compared to the A/G genotype. In the TCGA validation cohort, the altered group of IDH1 were significantly associated with better OS (HR: 0.35, 95% CI: 0.24-0.50, p-value&lt;0.001), DFS (HR: 0.34, 95% CI: 0.23-0.50, p-value&lt;0.001) , and PFS (HR: 0.43, 95% CI: 0.30-0.62, p-value&lt;0.001). The scRNA analysis showed predominant expression of IDH1, IDH2, and EGFR by malignant cells, oligodendrocyte precursor cells, and macrophages.
Conclusion: Our investigation into the genetic landscape of GBM within the Jordanian population suggest that specific genetic variants, particularly in IDH1 genes and EGFR, may serve as diagnostic and prognostic biomarkers for GBM. Additionally, IDH1 alterations were associated with better prognostic outcomes. Single-cell RNA analysis further illuminates the predominant expression of IDH1, IDH2, and EGFR by malignant cells which can be used as potential avenues for targeted therapies based on genetic profiles.
Citation Format: Ayah N. Al-Bzour, Sohaib M. Al-Khatib, Mohammad N. Almajali, Tariq A. Jarrad. Genetic variants of IDH and EGFR as diagnostic and prognostic biomarkers in glioblastoma multiforme: A case-control study in the Jordanian Arab population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5585.