Summary: definition and molecular etiology

Pediatric low-grade glioma (pLGG) is a heterogeneous group of WHO CNS grade 1 and 2 glial, glioneuronal, and neuronal tumors that account for 30% to 40% of pediatric CNS tumors. The 2021 fifth edition of the WHO classification (WHO CNS5) distributes these tumors across three families: pediatric-type diffuse low-grade gliomas (4 types, including diffuse low-grade glioma, MAPK pathway-altered), circumscribed astrocytic gliomas (including pilocytic astrocytoma, the most common type), and glioneuronal and neuronal tumors. Diagnosis is integrated and layered, combining histology with molecular findings.

The disease is driven predominantly by alterations that activate the RAS/MAPK pathway. In a population-based cohort from Toronto with molecular profiling of 477 tumors, a driver alteration was identified in 84%; KIAA1549-BRAF fusion was the most frequent alteration (35%), followed by BRAF p.V600E (17%), with germline NF1, FGFR1/2 (6.1%), and rare RAF1, NTRK2, ALK, and ROS1 alterations accounting for most of the remainder. Whole-genome sequencing of 96 pilocytic astrocytomas found MAPK pathway alterations in 100%. Germline NF1 is the main hereditary predisposition, with 15% to 20% of children with NF1 developing an optic pathway glioma.

Definition: pLGG as WHO grade 1 and 2 tumors, the most common childhood CNS tumor

“pLGG comprises 30%–40% of all pediatric CNS tumors, including a heterogeneous group of World Health Organization (WHO) grades 1 and 2 glioma, glioneuronal and neuronal neoplasms.” (opens the source at this quote in a new tab)
“Tumors that have historically been classified as pLGG now fall under several subcategories within the 2021 WHO glioma, glioneuronal, and neuronal tumor sections, including pediatric-type diffuse low-grade glioma, circumscribed astrocytic tumors, and glioneuronal and neuronal tumors (Table 1).” (opens the source at this quote in a new tab)
“For example, the most common type of pLGG, the pilocytic astrocytoma, remains a distinct entity, but it is now characterized as a type of circumscribed astrocytic tumor.” (opens the source at this quote in a new tab)

WHO CNS5 (2021): pediatric-type diffuse low-grade gliomas and circumscribed astrocytic gliomas

“WHO CNS5 has taken a new approach to classify the Gliomas, Glioneuronal Tumors, and Neuronal Tumors, and dividing them into 6 different families: (1) Adult-type diffuse gliomas (the majority of primary brain tumors in neuro-oncology practice of adults, eg, glioblastoma, IDH-wildtype); (2) Pediatric-type diffuse low-grade gliomas (expected to have good prognoses)” (opens the source at this quote in a new tab)
“For CNS5, the 4 types are Diffuse astrocytoma, MYB- or MYBL1-altered; Angiocentric glioma; Polymorphous low-grade neuroepithelial tumor of the young (often abbreviated as PLNTY; Figure 1); and Diffuse low-grade glioma, MAPK pathway-altered.” (opens the source at this quote in a new tab)
“For these tumors (as for most other glioma types), precise classification requires molecular characterization and the integration of histopathological and molecular information in a tiered diagnostic format. Clear delineation of the specific molecular features, in turn, sets the stage for targeted therapies of such tumors.” (opens the source at this quote in a new tab)
“Two specific aspects of CNS tumor grading have changed for WHO CNS5: Arabic numerals are employed (rather than Roman numerals) and neoplasms are graded within types (rather than across different tumor types).” (opens the source at this quote in a new tab)

WHO CNS5 (2021): key diagnostic genes for tumor types within the pLGG spectrum

Tumor type	Key diagnostic genes, molecules, pathways, or combinations
Pilocytic astrocytoma	“KIAA1549-BRAF, BRAF, NF1”
Diffuse low-grade glioma, MAPK pathway-altered	“FGFR1, BRAF”
Polymorphous low-grade neuroepithelial tumor of the young	“BRAF, FGFR family”
Pleomorphic xanthoastrocytoma	“BRAF, CDKN2A/B”
Diffuse astrocytoma, MYB- or MYBL1-altered	“MYB, MYBL1”
Angiocentric glioma	“MYB”

Etiology: RAS/MAPK pathway alterations in a cohort of more than 1,000 pLGG

“84% of cases harbored a driver alteration, while those without an identified alteration also often exhibited up-regulation of the RAS/MAPK pathway.” (opens the source at this quote in a new tab)
“KIAA1549-BRAF was the most frequent alteration in pLGG (35%) and was almost exclusively a single-event driver (n=175/180, 97%)” (opens the source at this quote in a new tab)
“BRAF p.V600E was the second most common alteration in pLGG (17%) and was frequently associated with additional alterations, most commonly deletion of CDKN2A (n=13, 9.6%) (Figure 2A).” (opens the source at this quote in a new tab)
“A further 1.3% (n=6) of cases contained alterations in other direct members of the RAS/MAPK pathway, including 3 RAF1 fusions, 2 KRAS mutations and one patient with a short deletion in MAP2K1” (opens the source at this quote in a new tab)
“Alterations in FGFR most frequently involved FGFR1/2 (n=29, 6.1%)” (opens the source at this quote in a new tab)
“as well as fusions involving ALK (n=2, 0.4%), ROS1 (n=2, 0.4%), and NTRK2 (n=2, 0.4%)” (opens the source at this quote in a new tab)
“In our study, NF1-driven pLGG accounted for 14% of cases (n=133).” (opens the source at this quote in a new tab)

Etiology: KIAA1549::BRAF fusion from tandem duplication at 7q34

“This rearrangement, which was not observed in a series of 244 higher-grade astrocytomas, results in an in-frame fusion gene incorporating the kinase domain of the BRAF oncogene. We further show that the resulting fusion protein has constitutive BRAF kinase activity, and is able to transform NIH3T3 cells.” (opens the source at this quote in a new tab)

“KIAA1549-BRAF accounts for 30-40% of pLGG at the population level” (opens the source at this quote in a new tab)

“Second, structural variants in the BRAF gene are the most common somatic driver event, found in approximately 70% of all sporadic pLGG.” (opens the source at this quote in a new tab)

“BRAF fusions, most commonly KIAA1549::BRAF, arise through tandem duplication at chromosome 7q34 and account for 60–80% of pilocytic astrocytomas (PAs) and approximately 15% of other pLGGs” (opens the source at this quote in a new tab)

Etiology: BRAF V600E frequency across histologies and locations

“BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice.” (opens the source at this quote in a new tab)
“As expected, the highest incidence of the mutation was observed in pleomorphic xanthoastrocytoma (78%) followed by gangliogliomas (49%); however, the mutation was also commonly observed in diffuse astrocytomas (43%) and WHO grade I astrocytomas (20%; Table 1).” (opens the source at this quote in a new tab)
“Overall, 33% of BRAF V600E PLGGs originated in the midline (diencephalon and brainstem).” (opens the source at this quote in a new tab)

Etiology: pilocytic astrocytoma as a single-pathway disease; FGFR1 and NTRK2 alterations

“We identified recurrent activating mutations in FGFR1 and PTPN11 and novel NTRK2 fusion genes in non-cerebellar tumors. New BRAF activating changes were also observed. MAPK pathway alterations affected 100% of tumors analyzed, with no other significant mutations, indicating pilocytic astrocytoma as predominantly a single-pathway disease.” (opens the source at this quote in a new tab)

“NTRK fusions, are identified in approximately 2% of pediatric gliomas overall” (opens the source at this quote in a new tab)

Etiology: neurofibromatosis type 1 as the principal predisposition syndrome

“10-15% of children with NF1 will develop a low-grade glioma within the optic pathway, with an additional 3-5% arising outside of the optic pathway” (opens the source at this quote in a new tab)

“Individuals with NF1 account for over 70% of the optic pathway/hypothalamic gliomas in children, and it is estimated that 15%–20% of all children with NF1 will develop an optic pathway glioma (OPG) during early childhood.” (opens the source at this quote in a new tab)

Company description of RAF alteration frequency

“Over the last decade, it has been found that between 50% and 60% of pLGGs are driven by abnormal signaling due to alterations in RAF, approximately 85% to 90% of which are a gene fusion known as KIAA1549-BRAF.” (opens the source at this quote in a new tab)
“In addition, between 5% and 17% of children with pLGGs have tumors with a BRAF V600E activating mutation.” (opens the source at this quote in a new tab)

Tovorafenib (DAY101)

Definition and etiology