Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Abstract

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

Low-grade glioneuronal tumour with novel molecular features associated with unusual partial epilepsy in a child

“…Paediatric low-grade gliomas are the most common brain tumours of childhood and are driven by genetic alterations in the RAS/mitogenactivated protein kinase pathway. [2][3][4] Two-thirds of Images in… paediatric low-grade gliomas contain alterations in NF1, BRAF-KIAA1549 fusions and BRAFV600E mutations. 3 However, mutations in FGFR, MYB and other single nucleotide variants and rearrangements have been identified.…”

“…[2][3][4] Two-thirds of Images in… paediatric low-grade gliomas contain alterations in NF1, BRAF-KIAA1549 fusions and BRAFV600E mutations. 3 However, mutations in FGFR, MYB and other single nucleotide variants and rearrangements have been identified. [2][3][4] Paediatric low-grade gliomas with gene rearrangements have improved progressionfree survivals than those with single nucleotide variants.…”

“…3 However, mutations in FGFR, MYB and other single nucleotide variants and rearrangements have been identified. [2][3][4] Paediatric low-grade gliomas with gene rearrangements have improved progressionfree survivals than those with single nucleotide variants. 3 The targeted mutations have led changes in management using biologics in the treatment of paediatric low-grade glioma.…”

“…[2][3][4] Paediatric low-grade gliomas with gene rearrangements have improved progressionfree survivals than those with single nucleotide variants. 3 The targeted mutations have led changes in management using biologics in the treatment of paediatric low-grade glioma. 5 The deletion involving exons 2-9 of BRAF, which includes the Rasbinding domain, has been described as a possible mechanism of resistance to B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) and Mitogen-activated protein kinase kinase (MEK) inhibition in other non-central nervous system tumours.…”

Neuropsychological impact of trametinib in pediatric low‐grade glioma: A case series

“…3 Recently, targeted therapies with specific RAS/mitogen-activated protein kinase (MAPK) inhibitors emerged as an attractive therapeutic option for PLGG not amenable to gross total resection, which shows superior tumor response compared to chemotherapy. [4][5] inhibitors, such as trametinib, block the MAPK pathway and are being investigated in patients with BRAF oncogene mutations and recurrent/refractory disease. 6 Early phase clinical trials are currently underway with data regarding trametinib toxicities emerging.…”