Papillary glioneuronal tumors: histological and molecular characteristics and diagnostic value of SLC44A1-PRKCA fusion

Abstract

IntroductionPapillary Glioneuronal Tumor (PGNT) is a grade I tumor which was classified as a separate entity in the World Health Organization Classification of the Central Nervous System 2007 in the group of mixed glioneuronal tumors. This tumor is rare and subclassifying PGNT represents a challenge. Recently, a fusion between SLC44A1 and PRKCA which encodes a protein kinase C involved in MAPK signaling pathway has been described in two studies (five cases). The current study aimed at raising the cytogenetic, histological and molecular profiles of PGNT and to determine if SLC44A1-PRKCA fusion represented a specific diagnostic marker to distinguish it from other glioneuronal tumors.ResultsWe report on four pediatric cases of PGNT, along with clinico-radiologic and immunohistological features for which SLC44A1-PRKCA fusion assessment by fluorescence in situ hybridization, BRAF V600E and FGFR1 mutation by immunohistochemistry and direct DNA sequencing and KIAA1549-BRAF fusion by RT-PCR were performed. MAPK signaling pathway activation was investigated using phospho-ERK immunohistochemistry and western blot. We analyzed fifteen cases of tumors with challenging histological or clinical differential diagnoses showing respectively a papillary architecture or periventricular location (PGNT mimics). fluorescence in situ hybridization analysis revealed a constant SLC44A1-PRKCA fusion signal in all PGNTs. None of PGNT mimics showed the SLC44A1-PRKCA fusion signal pattern. All PGNTs were negative for BRAF V600E and FGFR1 mutation, and KIAA1549-BRAF fusion. Phospho-ERK analysis provides arguments for the activation of the MAPK signaling pathway in these tumors.ConclusionsHere we confirmed and extended the molecular data on PGNT. These results suggest that PGNT belong to low grade glioma with MAPK signaling pathway deregulation. SLC44A1-PRKCA fusion seems to be a specific characteristic of PGNT with a high diagnostic value and detectable by FISH.

Low-grade developmental and epilepsy associated brain tumors: a critical update 2020

“…A PRKCA (9; 17)(q31;q24) translocation was first identified in 2013 by Bridge and coworkers in two PGNT and the respective SLC44A1-PRKCA fusion detected by RT-PCR and FISH analysis [11]. This was confirmed within four pediatric cases of PGNT through FISH analysis whilst 15 PGNT mimics showed no fusion [50]. More recently, Hou et al [31] looked at 28 PGNTs by using the DNA methylation array approach and performed a hierarchical cluster analysis comparing with 130 reference cases from 13 distinct methylation classes.…”

EWSR1‐PATZ1 gene fusion may define a new glioneuronal tumor entity

“…For the last ten years, NGS has allowed the rapid discovery of new molecular alterations that ascertain the diagnosis of several glioneuronal tumors. Some alterations are pathognomonic for a tumor entity as SLC44A1‐PRKCA fusion gene for PGNT ; others are associated with two or more entities, as FGFR1 mutations associated at least with DNET, rosette forming glioneuronal tumor and pilocytic astrocytoma . It seems crucial to put our Case 1 into the molecular context of glioneuronal tumors .…”

“…They can confirm the diagnosis of some tumor entities or give strong indications for a certain diagnosis for others. For example, the SLC44A1 (solute carrier family 44, member 1)‐ PRKCA (protein kinase C alpha) fusion gene has been shown to be associated with PGNT and almost pathognomonic of this diagnosis . The BRAF V600E mutation is a useful diagnostic marker in ganglioglioma , even if some of its differential diagnoses such as dysembryoplastic neuroepithelial tumor (DNET) can exhibit this mutation .…”

Biomarkers in tumors of the central nervous system – a review

“…However, different alterations in the PRKCA gene have been reported in two other CNS tumor entities; PRKCA D294G mutations in pituicytomas and the SLC44A1-PRKCA gene fusions in papillary glioneuronal tumors (101)(102)(103). The latter fusion seems to be a specific biomarker for papillary glioneuronal tumors, alters the MAPK pathway, and can be detected by FISH analysis (103,104).…”