Molecular convergence enables precision medicine for pediatric low grade gliomas

Pediatric low-grade gliomas are the most common CNS tumors in children, comprising heterogeneous WHO grade 1–2 neoplasms. Despite histologic diversity, these tumors show remarkable molecular convergence with near-universal RAS/MAPK pathway activation, typically driven by single oncogenic alterations. The most frequent molecular alterations include BRAF abnormalities (V600E mutations, KIAA1549-BRAF fusions) and FGFR alterations. Most tumors occur sporadically, though some arise in cancer predisposition syndromes, particularly neurofibromatosis type 1 and tuberous sclerosis complex. Clinical presentation varies by tumor location and patient age, with common symptoms including headache, seizures, visual disturbances, and elevated intracranial pressure. Gross total resection remains the preferred treatment when feasible, achieving cure in most cases. However, tumors in eloquent regions often preclude complete resection, necessitating systemic therapy. Historically, carboplatin-vincristine combination served as first-line systemic treatment. Molecularly targeted agents have transformed the therapeutic landscape, with BRAF and MEK inhibitors showing superior efficacy in molecularly defined subgroups. DaBRAFenib plus trametinib received approval for newly diagnosed BRAF V600E-mutant tumors, while tovorafenib was approved for relapsed/refractory BRAF-altered disease. Despite excellent 20-year overall survival approaching 90%, approximately half demonstrate progression or recurrence, requiring multiple interventions and resulting in substantial long-term morbidity. Future directions include routine molecular profiling, treatment sequencing optimization, biomarker development, and resistance mechanism studies, aiming to transform this into effectively controlled disease with minimal developmental impact.