Rosette‐forming glioneuronal tumours are midline, FGFR1‐mutated tumours

Abstract

Aim: Rosette-forming glioneuronal tumour (RGNT) is a rare central nervous system (CNS) World Health Organization (WHO) grade 1 brain neoplasm. According to the WHO 2021, essential diagnostic criteria are a 'biphasic histomorphology with neurocytic and a glial component, and uniform neurocytes forming rosettes and/or perivascular pseudorosettes associated with synaptophysin expression' and/or DNA methylation profile of RGNT whereas 'FGFR1 mutation with co-occurring PIK3CA and/or NF1 mutation' are desirable criteria. Material and methods: We report a series of 46 cases fulfilling the essential pathological diagnostic criteria for RGNT. FGFR1 and PIK3CA hotspot mutations were searched for by multiplexed digital PCR in all cases, whereas DNA methylation profiling and/or PIK3R1 and NF1 alterations were analysed in a subset of cases. Results: Three groups were observed. The first one included 21 intracranial midline tumours demonstrating FGFR1 mutation associated with PIK3CA or PIK3R1 (n = 19) or NF1 (n = 1) or PIK3CA and NF1 (n = 1) mutation. By DNA methylation profiling, eight cases were classified as RGNT (they demonstrated FGFR1 and PIK3CA or PIK3R1 mutations). Group 2 comprised 11 cases associated with one single FGFR1 mutation. Group 3 included six cases classified as low-grade glioma (LGG) other than RGNT (one-sixth showed FGFR1 mutation and one a FGFR1 and NF1 mutation) and eight cases without FGFR1 mutation. Groups 2 and 3 were enriched in lateral and spinal cases. Conclusions: We suggest adding FGFR1 mutation and intracranial midline location as essential diagnostic criteria. When DNA methylation profiling is not available, a RGNT diagnosis remains certain in cases demonstrating characteristic pathological features and FGFR1 mutation associated with either PIK3CA or PIK3R1 mutation.

The landscape of common genetic drivers and DNA methylation in low‐grade (epilepsy‐associated) neuroepithelial tumors: A review

“…The RGNT harbored a distinct epigenetic signature compared with other LNETs, and was associated to FGFR1 mutation with co‐occurring PIK3CA and/or NF1 mutation 7,39,101 . Lucas et al .…”

Clinico-pathological and epigenetic heterogeneity of diffuse gliomas with FGFR3::TACC3 fusion

“…These cases were retrieved from 8 University Hospital Centers: GHU Paris Psychiatry and Neurosciences, Marseille, Lille, Lyon, Toulouse, Nice, Montpellier and Rennes. Three cases (#13, #16 and #19) have been previously reported [ 2 , 23 ]. Written informed consent to be included in this study was provided by the participants or participants’ legal guardian/next of kin.…”

Pediatric low-grade glioma models: advances and ongoing challenges

“…FGFR1 hotspot mutations mainly consist of N546K (Asparagine to Lysine) and K656E (Lysine to Glutamic acid). These mutations are most commonly found in midline tumors such as dysembryoplastic neuroepithelial tumors (DNETs ( 10 , 19 , 38 – 40 ), but they have been reported in posterior fossa PA with widespread oligodendroglial features ( 15 ), extracerebellar PA ( 19 ), RGNTs ( 16 , 17 ) and diffuse midline gliomas along with H3K27M mutations ( 41 ). These FGFR1 hotspot mutations can also co-occur with other genetic alterations including NF1 , other FGFR1 point mutations or other RAS/MAPK pathway alterations ( 10 , 13 ).…”