| Summary: | Gliomas are the most common malignant brain tumors with high mortality rates. Recently we showed that the <i>FREM2</i> gene has a role in glioblastoma progression. Here we reconstructed the <i>FREM2</i> molecular pathway using the human interactome model. We assessed the biomarker capacity of <i>FREM2</i> 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 <i>FREM2</i> pathway showed strong biomarker characteristics and significantly outperformed the <i>FREM2</i> expression level itself. For all relevant datasets, it could robustly discriminate GBM and LGG (<i>p</i> < 1.63 × 10<sup>−13</sup>, AUC > 0.74). High <i>FREM2</i> pathway activation level was associated with poor OS in LGG (<i>p</i> < 0.001), and low PFS in LGG (<i>p</i> < 0.001) and GBM (<i>p</i> < 0.05). <i>FREM2</i> pathway activation level was poor prognosis biomarker for OS (<i>p</i> < 0.05) and PFS (<i>p</i> < 0.05) in LGG with <i>IDH</i> mutation, for PFS in LGG with wild type <i>IDH</i> (<i>p</i> < 0.001) and mutant <i>IDH</i> with 1p/19q codeletion(<i>p</i> < 0.05), in GBM with unmethylated <i>MGMT</i> (<i>p</i> < 0.05), and in GBM with wild type <i>IDH</i> (<i>p</i> < 0.05). Thus, we conclude that the activation level of the <i>FREM2</i> pathway is a potent new-generation diagnostic and prognostic biomarker for multiple molecular subtypes of GBM and LGG.
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