| Summary: | World Health Organization grade IV diffuse gliomas, known as glioblastomas, are the most common malignant brain tumors, and they show poor prognosis. Multimodal treatment of surgery followed by radiation and chemotherapy is not sufficient to increase patient survival, which is 12 to 18 months after diagnosis. Despite extensive research, patient life expectancy has not significantly improved over the last decade. Previously, we identified <i>FREM2</i> and <i>SPRY1</i> as genes with differential expression in glioblastoma cell lines compared to nonmalignant astrocytes. In addition, the <i>FREM2</i> and <i>SPRY1</i> proteins show specific localization on the surface of glioblastoma cells. In this study, we explored the roles of the <i>FREM2</i> and <i>SPRY1</i> genes and their proteins in glioblastoma pathology using human tissue samples. We used proteomic, transcriptomic, and bioinformatics approaches to detect changes at different molecular levels. We demonstrate increased FREM2 protein expression levels in glioblastomas compared to reference samples. At the transcriptomic level, both <i>FREM2</i> and <i>SPRY1</i> show increased expression in tissue samples of different glioma grades compared to nonmalignant brain tissue. To broaden our experimental findings, we analyzed The Cancer Genome Atlas glioblastoma patient datasets. We discovered higher <i>FREM2</i> and <i>SPRY1</i> gene expression levels in glioblastomas compared to lower grade gliomas and reference samples. In addition, we observed that low <i>FREM2</i> expression was associated with progression of <i>IDH</i>-mutant low-grade glioma patients. Multivariate analysis showed positive association between <i>FREM2</i> and favorable prognosis of <i>IDH</i>-wild type glioblastoma. We conclude that <i>FREM2</i> has an important role in malignant progression of glioblastoma, and we suggest deeper analysis to determine its involvement in glioblastoma pathology.
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