Unique Molecular Landscapes Distinguish Low- and High-Grade NF1 Gliomas

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome characterized by germline mutations in the NF1 gene encoding neurofibromin, a negative regulator of RAS. NF1 is associated with an increased risk of gliomas, with low-grade gliomas more common in children and high-grade gliomas more prevalent in adults. To assess the genetic and epigenetic landscape of NF1 gliomas and compare this molecular profile to that of sporadic gliomas, D'Angelo, Ceccarelli, and colleagues performed whole-exome sequencing, RNA sequencing, and DNA methylation analysis of a cohort of NF1 glioma samples consisting of both low- and high-grade gliomas. Pediatric low-grade NF1 gliomas exhibited few recurrent somatic mutations, which occurred primarily in genes involved in MAPK signaling. However, a subset of low-grade tumors was characterized by increased infiltration of cytolytic effector CD8⁺ T cells, expression of mutation-derived neoantigens with enhanced HLA binding, and activation of immune-related signatures as a result of decreased DNA methylation of immune genes. In contrast, high-grade NF1 gliomas in adults exhibited a significantly higher mutation burden, including genetic alterations in genes involved in transcription and chromatin regulation and the PI3K pathway. In particular, high-grade gliomas frequently harbored copy-number loss of CDKN2A/B together with inactivating mutations in TP53 and the chromatin remodeling gene ATRX. Consistent with this finding, high-grade NF1 gliomas displayed loss of ATRX protein expression and induction of an alternative lengthening of telomeres phenotype. Integrative analyses of DNA methylation profiles revealed that NF1 gliomas recapitulate molecular features of the LGm6 IDH–wild-type subgroup of sporadic gliomas defined by The Cancer Genome Atlas, which are characterized by frequent somatic mutations in NF1, TP53, and ATRX. Taken together, these data identify genetic and epigenetic alterations that distinguish low- and high-grade NF1 gliomas and provide further insights into the classification of sporadic gliomas.

D'Angelo F, Ceccarelli M, Tala, Garofano L, Zhang J, Frattini V, et al. The molecular landscape of glioma in patients with neurofibromatosis 1. Nat Med 2019;25:176–87.

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