Molecular Drivers in pLGG: Impact on Prognosis and Treatment Choices

Molecular profiling has become a cornerstone in the diagnosis and management of pLGGs. Although these tumors may vary histologically and clinically, they tend to converge on a shared biologic driver—dysregulation of the MAPK signaling pathway. This unifying characteristic makes molecular testing crucial, as it informs both prognosis and treatment planning. When tissue samples are available through biopsy or resection, the molecular data they yield help guide individualized approaches to care.

Among the most common molecular alterations are BRAF fusions, particularly KIAA1549-BRAF, and point mutations such as BRAF V600E. The BRAF fusion is more frequently associated with a favorable prognosis, whereas the BRAF V600E mutation—especially when coupled with alterations such as CDKN2A deletion—may indicate a higher risk of progression and resistance to conventional therapies. Other mutations along the MAPK pathway, including those in KRAS, FGFR , and NTRK genes, also play a role in tumor development, offering additional targets for emerging treatments.

The growing understanding of these molecular drivers has led to the development of targeted therapies, such as BRAF and MEK inhibitors, which have shown promising clinical activity. These advances offer new hope for children with tumors that are not amenable to surgery or that recur after initial treatment. Ultimately, although the tumors are molecularly diverse, their convergence on a common pathway provides a clear therapeutic framework. The integration of molecular data into clinical decision-making is shaping a more personalized, effective, and less-toxic approach to pediatric neuro-oncology care.