Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology

Abstract

Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.

Keywords: BRAF; FGFR1; Glioma; Glioneuronal; MYB; RNA-seq.

Figure 1

Genetic alterations among 42 LGNTs with an oligodendroglial phenotype (a). FGFR1 SNVs represented on the protein structure and tabulated, including four tumors with ‘doublet’ missense mutations on the same allele – lower part of diagram – and one tumor with two mutations, each on a different allele – upper part of diagram, with single mutations (b).

Figure 2

Genetic alterations among 32 LGNTs with an astrocytic phenotype (a). Location of MYB fusion genes represented on protein structure (b). LGNT73 - iFISH profiles using MYB and QKI ‘break-apart’ probe sets and demonstrating rearrangement/deletion of QKI, but not MYB.

Figure 3

Genetic alterations among 17 gangliogliomas (a). WGS, WES, or RNA-seq data were available for 15/17 tumors; LGNT83 and LGNT87 were analyzed by targeted approaches but not by NGS. Of nine gangliogliomas with BRAF alterations, six had a BRAF:p.V600E mutation. EWSR1-PATZ1 fusion (b). Two clones, differing only with respect to a 3-bp deletion (‘del’ over sequence trace), were independently validated. In the rearrangement, PATZ1 loses its transcriptional repressor domain (BTB/POZ domain) at the N-terminus.

Figure 4

DNA methylation-based data from LGNTs with BRAF, FGFR1, or MYB/MYBL1 pathogenic alterations used in unsupervised hierarchical clustering (a), or principal components analysis (b). AG, angiocentric glioma; DA, diffuse astrocytoma; DNET, dysembryoplastic neuroepithelial tumor; O, oligodendroglioma; OA, oligoastrocytoma; GG, ganglioglioma; Astro, astrocytic; d-OT, diffuse oligodendroglial tumor.

Figure 5

Proportions of key genetic alterations in four types of LGNT divided into two axes according to histogenesis – astrocytic and oligodendroglial. AG, angiocentric glioma; DA, diffuse astrocytoma; DNET, dysembryoplastic neuroepithelial tumor; d-OTs, diffuse oligodendroglial tumors.