Pediatric low-grade glioma in the era of molecular diagnostics

Abstract

Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behaviorin particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.

Loss of efficacy of subsequent nonsurgical therapy after primary treatment failure in pediatric low‐grade glioma patients—Report from the German SIOP‐LGG 2004 cohort

“…The pattern rather corresponds to more aggressive tumor types not identifiable by conventional histologic criteria, up to now. 38,[49][50][51][52][53]…”

Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma

“…Interestingly, the presence of T-cells within tumors was inversely correlated with the expression of SOX2 ( online supplementary figure 1B ). Although most pediatric LGG share activation of the BRAF-MAPK pathway as a common genomic alteration, 8 the mechanism underlying BRAF activation in PXA/GG is commonly the V600E mutation, while BRAF-KIAA1549 fusion is observed in PAs. 8 T-cells against driver mutations have been limited in some settings, presumably due to selection based on HLA genotype.…”

“…Although most pediatric LGG share activation of the BRAF-MAPK pathway as a common genomic alteration, 8 the mechanism underlying BRAF activation in PXA/GG is commonly the V600E mutation, while BRAF-KIAA1549 fusion is observed in PAs. 8 T-cells against driver mutations have been limited in some settings, presumably due to selection based on HLA genotype. 21 In order to test whether the BRAF V600E mutation could be immunogenic in pediatric tumors, we synthesized peptides encompassing this mutation and used these to detect and expand BRAF V600E -specific T-cells in culture.…”

BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young

“…Pediatric low-grade neuroepithelial tumors (P-LGNTs) encompass a group of central nervous system neoplasms that includes long-term epilepsy-associated tumors (LEATs), such as ganglioglioma and dysembryoplastic neuroepithelial tumor (DNT). P-LGNTs have different characteristics than their adult counterparts, and are commonly driven by genomic alterations in the Ras/mitogen-activated protein kinase (MAPK) pathway, such as mutations in BRAF and NF - 1 [ 23 , 29 ]. Recent large-scale genomic studies and genome-wide methylation analyses allowed a thorough characterization of P-LGNTs [ 24 ], and cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) currently classifies P–LGNTs as distinct disease entities [ 4 , 17 ].…”