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

María Jesús Lobón-Iglesias; Ingrid Laurendeau; Léa Guerrini-Rousseau; Arnault Tauziède-Espariat; Audrey Briand-Suleau; Pascale Varlet; Dominique Vidaud; Michel Vidaud; Laurence Brugieres; Jacques Grill; Eric Pasmant

doi:10.1093/noajnl/vdz054

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

Neurooncol Adv. 2019 Dec 20;2(Suppl 1):i98-i106. doi: 10.1093/noajnl/vdz054. eCollection 2020 Jul.

Authors

María Jesús Lobón-Iglesias^{1

2}, Ingrid Laurendeau², Léa Guerrini-Rousseau^{1

3}, Arnault Tauziède-Espariat⁴, Audrey Briand-Suleau^{2

5}, Pascale Varlet⁴, Dominique Vidaud^{2

5}, Michel Vidaud^{2

5}, Laurence Brugieres^{1

3}, Jacques Grill^{1

3}, Eric Pasmant^{2

5}

Affiliations

¹ Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8203 and Université Paris Saclay, Villejuif, France.
² INSERM U1016, Cochin Institute, Paris Descartes University, Sorbonne Paris Cité, CARPEM, Paris, France.
³ Gustave Roussy, Département de Cancérologie de l'Enfant et de l'Adolescent, Villejuif, France.
⁴ Centre Hospitalier Sainte-Anne, Laboratoire de Neuropathologie, Paris, France.
⁵ Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.

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.