In Lower‐Grade Gliomas, the SPARC Family Exacerbates Prognosis by Influencing Immunity, Stemness, and Metabolism

Background Involvement of the SPARC stromal protein family in crucial biological regulatory mechanisms is well‐documented. But understanding the consequences of imbalanced SPARC protein activity in lower‐grade glioma (LGG) is still emerging. Aims Examining the clinical significance of SPARC proteins, researchers employed RNA‐seq data from diverse patient groups to gain insight. A novel SPARCScore was developed via LASSO regression analysis, leveraging data from the PanCanAtlas and MEXPRESS to shed light on the molecular mechanisms involved. Methods and Results Our findings indicate that a majority of SPARC family proteins show atypical expression levels, correlating significantly with adverse outcomes in LGG. Our construction of an SPARCscore, indicative of the SPARC family's presence, revealed a direct correlation between a high SPARCscore and worsened tumor prognosis, irrespective of radiotherapy or chemotherapy treatments. The SPARCScore risk groups showed distinct drivers: PIK3CA predominantly influenced the low‐risk category, whereas EGFR was a key factor in the high‐risk group. High SPARCScore tumors exhibited a mutation profile similar to glioblastoma, marked by reduced methylation and diverse glioma stem cells (GSC). Conversely, the low SPARCScore tumors were characterized by increased methylation and limited GSC variety. Furthermore, the high‐SPARCScore group was notable for its pronounced inflammatory and extracellular matrix signatures, along with activated metabolic pathways. These patterns were closely linked to prognosis. Conclusion In essence, this research highlights the significance of SPARC proteins in LGG, offering insights into promising avenues for targeted therapy.