Abstract Background Targeting the Ras/MAPK pathway is driving a paradigm shift in pediatric low-grade glioma (pLGG) treatment. Despite their slow growth, tumors often recur, and many patients undergo multiple and prolonged lines of treatment. Most treatment decisions are based on the analyses of the primary tissue, and the mechanisms driving tumor progression remain unclear. Methods We analyzed the molecular profiles of 130 tumor samples from 109 patients with pLGG 17 patients with matched samples. Using imaging mass cytometry (IMC), we compared single-cell phenotypes and the spatial cytoarchitecture of primary and matched recurrent pLGGs. Results BRAF alterations were observed in 53% of patients, with rare BRAF fusion variants, and PTPN11 and PIK3CA alterations enriched in patients with progressive disease. In matched primary/recurrent samples, new genetic alterations were detected in 14/21 samples at progression, particularly in patients who received non-surgical treatments, suggesting the emergence or selection of neoplastic subpopulations during chemo/radiotherapy. Using 70 unique protein markers we profiled 782934 cells using IMC to capture the tumor, immune, and stromal compartments from 53 pLGG samples. We observed a complex tumor microenvironment with substantial inter- and intra-patient heterogeneity, including up to 30% non-neoplastic cells. GFAP,Vimentin+ cells were significantly more abundant in recurrent samples, particularly within reactive regions, and exhibited significant cellular interactions with GFAP,S100B+ cells and tumor-associated macrophages/microglia. Conclusion Molecular characterization of progressive pLGGs can reveal additional alterations with potential treatment implications, underscoring the importance of re-biopsy in patients with progressive disease. Spatial analyses of tumor cell phenotypes are critical for understanding the variability between primary and recurrent disease, potentially offering clinically actionable insights into treatment failure in pLGG.
Machaalani et al. (Tue,) studied this question.