Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1

Abstract

Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this lowgrade glioneuronal entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening amongst a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two thirds of the cases (63%). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33%). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease.

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…A graphical summary of the evolution of the field within the context of brain tumours is displayed in Figure . DNA methylation is further gaining importance for tumour entity definition and is increasingly being used for the allocation of rare cancers into either known tumour classes or the identification of new entities , a collection of which are summarized in Figure .…”

“…Among paediatric low‐grade gliomas and glioneuronal tumours, at least nine main DNA methylation classes have so far been established and seem sufficiently distinct for tumour classification . The molecular classes are clearly related to the established histological tumour classes although there is typically some degree of reallocation when molecular classes are overlaid on histological series . Figure lists the main molecular classes.…”

FGFR- gene family alterations in low-grade neuroepithelial tumors

“…It is on the basis of histology that the diagnosis is rendered. While in recent studies FGFR1 hotspot mutations were invariably detected among RGNTs [66], their presence is not currently required for the diagnosis, (and as previously discussed, is certainly not unique to RGNT). Moreover, while RGNT corresponds histologically to WHO grade I and is generally considered benign, dissemination and progression have been reported in rare instances [1,2,62,68,74].…”

“…FGFR1 hotspot mutations have also emerged as a molecular hallmark of rosette-forming glioneuronal tumor (RGNT) [26,66]. RGNTs predominately affect young adults and are relatively rare neuroepithelial tumors with distinctive histologic features namely, the presence of neurocytes in rosettes or perivascular pseudo-rosettes in addition to an astrocytic component resembling pilocytic astrocytoma.…”

“…Moreover, while RGNT corresponds histologically to WHO grade I and is generally considered benign, dissemination and progression have been reported in rare instances [1,2,62,68,74]. Of note, frequent comutation with PIK3CA as well as NF1 have been reported in RGNT [66]. Mutation of PI3K pathway genes has been associated with aggressive clinical behavior in…”