Abstract
PurposeLow-grade gliomas (LGG) and mixed neuronal-glial tumors (MNGT) show frequent MAPK pathway alterations. Oncogenic fibroblast growth factor receptor 1 (FGFR1) tyrosinase kinase domain has been reported in brain tumors of various histologies. We sought to determine the frequency of FGFR1 hotspot mutations N546 and K656 in driver-unknown LGG/MNGT and examined FGFR1 immunohistochemistry as a potential tool to detect those alterations.MethodsWe analyzed 476 LGG/MNGT tumors for KIAA-1549-BRAF fusion, IDH1/2, TERT promotor, NF1, H3F3A and the remaining cases for FGFR1 mutation frequency and correlated FGFR1 immunohistochemistry in 106 cases.Results368 of 476 LGG/MNGT tumors contained non-FGFR1 alterations. We identified 9 FGFR1 p.N546K and 4 FGFR1 p.K656E mutations among the 108 remaining driver-unknown samples. Five tumors were classified as dysembryoplastic neuroepithelial tumor (DNT), 4 as pilocytic astrocytoma (PA) and 3 as rosette-forming glioneuronal tumor (RGNT). FGFR1 mutations were associated with oligodendroglia-like cells, but not with age or tumor location. FGFR1 immunohistochemical expression was observed in 92 cases. FGFR1 immunoreactivity score was higher in PA and DNT compared to diffuse astrocytoma, but no correlation between FGFR1 mutation in tumors and FGFR1 expression level was observed.ConclusionFGFR1 hotspot mutations are the fifth most prevailing alteration in LGG/MNGT. Performing FGFR1 sequencing analysis in driver-unknown low-grade brain tumors could yield up to 12% FGFR1 N546/K656 mutant cases.
Highlights
Low-grade gliomas (LGG) and the WHO category of mixed neuronal-glial tumors (MNGT) encompass a broad spectrum of mostly pediatric tumors with usually indolent clinical behavior or long-term epilepsy-associated sequelae (Surrey et al 2019)
108 samples without entity-defining molecular alterations were analyzed for fibroblast growth factor receptor 1 (FGFR1) hotspot mutations in pyrosequencing (Fig. 1A) and in 105 cases the signal passed quality checks
Among the p.N546K mutated cases, three tumors were diagnosed as dysembryoplastic neuroepithelial tumor (DNT), four tumors as pilocytic astrocytoma (PA), one tumor as rosette-forming glioneuronal tumor (RGNT) and the remaining tumor only had a descriptive diagnosis of low-grade neuroepithelial tumor
Summary
Low-grade gliomas (LGG) and the WHO category of mixed neuronal-glial tumors (MNGT) encompass a broad spectrum of mostly pediatric tumors with usually indolent clinical behavior or long-term epilepsy-associated sequelae (Surrey et al 2019). The most frequent single driver alterations in these tumors are a v-Raf murine sarcoma viral oncogene homolog B (BRAF) V600E mutation, a fibroblast growth factor receptor (FGFR) alteration, or a v-Myb avian myeloblastosis viral oncogene homolog (MYB) or MYBL1 rearrangement which are all associated with a rather favourable outcome (Qaddoumi et al 2016; Yang et al 2018). These driving genetic alterations are usually conserved at tumor recurrence (Lazow et al 2020). FGFR1 alterations are not restricted to tumor grade or a specific age group (Bale 2020)
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