NF1-like optic pathway gliomas in children: clinical and molecular characterization of this specific presentation

Abstract

Background: Pediatric neurofibromatosis type 1 (NF1)-associated optic pathway gliomas (OPGs) exhibit different clinico-radiological features, treatment, and outcome compared with sporadic OPGs. While NF1-associated OPGs are caused by complete loss-of-function of the NF1 gene, other genetic alterations of the RAS-MAPK pathway are frequently described in the sporadic cases. We identified a group of patients who presented OPGs with typical radiological features of NF1-associated OPGs but without the NF1 diagnostic criteria. We aim to investigate into the possible molecular mechanisms underlying this "NF1-like" pediatric OPGs presentation.

Methods: We analyzed clinico-radiological features of 16 children with NF1-like OPGs and without NF1 diagnostic criteria. We performed targeted sequencing of the NF1 gene in constitutional samples (n = 16). The RAS-MAPK pathway major genes were sequenced in OPG tumor samples (n = 11); BRAF FISH and IHC analyses were also performed.

Results: In one patient's blood and tumor samples, we identified a NF1 nonsense mutation (exon 50: c.7285C>T, p.Arg2429*) with ~8% and ~70% VAFs, respectively, suggesting a mosaic NF1 mutation limited to the brain (segmental NF1). This patient presented signs of neurodevelopmental disorder. We identified a somatic alteration of the RAS-MAPK pathway in eight tumors: four BRAF activating p.Val600Glu mutations, three BRAF:KIAA oncogenic fusions, and one putative gain-of-function complex KRAS indel inframe mutation.

Conclusions: NF1-like OPGs can rarely be associated with mosaic NF1 that needs specific constitutional DNA analyses for diagnosis. Further studies are warranted to explore unknown predisposition condition leading to the NF1-like OPG presentation, particularly in patients with the association of a neurodevelopmental disorder.

Keywords: BRAF fusion; NF1; mosaicism; pediatric optic pathway glioma; pilocytic astrocytoma; segmental neurofibromatosis.

Figure 1.

Axial FLAIR images showing infiltrative OPG spreading at the entire optic pathway corresponding to patients P1 (A, B), P6 (C, D), P7 (E, F), and P9 (G, H). Axial FLAIR images showing OPG mainly localized at chiasm with slight bilateral changes (arrows) at the optic radiation fibers corresponding to patients P14 (I, J) and P15 (K, L).

Figure 2.

Axial FLAIR (A, B, D) and contrast-enhanced (C) images showing an OPG with major extra-optic component corresponding to patients P2 (A, B) and P11 (C, D).

Figure 3.

(A) Image extracted from Integrative Genomics Viewer showing NF1 mutation at exon 50: c.7285C>T, p.Arg2429* in blood (left) and tumor (right) samples. (B) Image extracted from IGV showing the complex KRAS exon 3 mutation: c.197_203delins13, p.Ala66_Arg68delinsAspCysThrValLeu in tumor sample of patient P11.