Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas

SIMPLE SUMMARY: Gliomas are the most common malignant brain tumors with high mortality rates. Recently the role of the FREM2 gene has been shown in glioblastoma progression. Here we reconstructed the FREM2 molecular pathway. We assessed the biomarker capacity of FREM2 expression and its pathway as the overall survival (OS) and progression-free survival (PFS) biomarkers. We used 566 glioblastomas (GBM) and 1097 low-grade gliomas (LGG) to test these biomarkers. FREM2 molecular pathway was a better biomarker than FREM2 gene expression. It could robustly discriminate between GBM and LGG. High FREM2 pathway activation level was associated with poor overall survival (OS) in LGG, and low progression-free survival in LGG and GBM. FREM2 pathway activation level was also a poor prognosis biomarker for OS and PFS in LGG with IDH mutation, for PFS in LGG with wild type IDH and mutant IDH with 1p/19q codeletion, in GBM with unmethylated MGMT, and in GBM with wild type IDH. ABSTRACT: Gliomas are the most common malignant brain tumors with high mortality rates. Recently we showed that the FREM2 gene has a role in glioblastoma progression. Here we reconstructed the FREM2 molecular pathway using the human interactome model. We assessed the biomarker capacity of FREM2 expression and its pathway as the overall survival (OS) and progression-free survival (PFS) biomarkers. To this end, we used three literature and one experimental RNA sequencing datasets collectively covering 566 glioblastomas (GBM) and 1097 low-grade gliomas (LGG). The activation level of deduced FREM2 pathway showed strong biomarker characteristics and significantly outperformed the FREM2 expression level itself. For all relevant datasets, it could robustly discriminate GBM and LGG (p < 1.63 × 10(−13), AUC > 0.74). High FREM2 pathway activation level was associated with poor OS in LGG (p < 0.001), and low PFS in LGG (p < 0.001) and GBM (p < 0.05). FREM2 pathway activation level was poor prognosis biomarker for OS (p < 0.05) and PFS (p < 0.05) in LGG with IDH mutation, for PFS in LGG with wild type IDH (p < 0.001) and mutant IDH with 1p/19q codeletion(p < 0.05), in GBM with unmethylated MGMT (p < 0.05), and in GBM with wild type IDH (p < 0.05). Thus, we conclude that the activation level of the FREM2 pathway is a potent new-generation diagnostic and prognostic biomarker for multiple molecular subtypes of GBM and LGG.