Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

Abstract

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modelling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1%) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19%; p<0.0001) and hotspot BRAF p.V600E (12/53; 22.6%) (p<0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.

FGFR1 N546K and H3F3A K27M mutations in a diffuse leptomeningeal tumour with glial and neuronal markers

“…Recently, the FGFR1 N546K mutation was reported in a case of papillary GNT, and it has subsequently been reported in two cases of rosette‐forming GNT . The FGFR1 N546K mutation has also been reported in pilocytic astrocytomas and dysembryoplastic neuroepithelial tumours (another entity composed of oligodendroglioma‐like cells showing glial and neuronal positivity) . This case shows the same FGFR1 mutation in a diffuse leptomeningeal tumour with glial and neuronal features, but also shows the presence of the H3F3A K27M mutation.…”

Dysembryoplastic neuroepithelial tumour: insight into the pathology and pathogenesis

“…Furthermore, high frequency of FGFR1 mutations was presented by Rivera et al [56]. Interestingly, they distinguished two groups of tumours from collected samples, which were primarily diagnosed as DNTs.…”

“…It was localized in the region coding tyrosine kinase domain. The tumours, which were resected from proband's children, shared somatic "hot spot" mutations [56].…”

Exploiting Molecular Biology for Diagnosis and Targeted Management of Pediatric Low-Grade Gliomas

“…(Figure 1 D). The BRAF V600E mutation is present in 15–51% of DNT [41], and FGFR1 alterations are present in 58–82% [42] [14]. Radiographically these tumors usually are not associated with mass effect or peritumoral edema.…”