Immune microenvironment and lineage tracing help deciphering Rosette-forming GlioNeuronal Tumors: a multi-omic analysis of 9 cases

Rosette-forming GlioNeuronal Tumor (RGNT) is a rare central nervous system neoplasm containing two components, glial and neuronal. The delineation of histological diagnosis of RGNT from similar low-grade tumors such as pilocytic astrocytoma (PA) and ganglioglioma (GG) may be challenging. We performed here a comprehensive molecular analysis of a cohort of tumors with same histology features to identify molecular characteristics of RGNT.
A cohort of 9 rosette-forming tumors histologically-diagnosed were analyzed at molecular level using multimodal approaches as Whole Exome Sequencing (WES), RNAseq and methylome. In our cohort, 3 tumors were plotted within the Methylation Class-RGNT (MC-RGNT) characterized by FGFR1 mutation associated with PIK3CA or NF1 mutations. Transcriptome analysis was performed in 7 cases. RNAseq identified a “Hot†and a “Cold†transcriptomic group; the latter includes the 3 MC-RGNT and 1 MC-Pilocytic Astrocytoma and exhibited a “Cold†immune tumor microenvironment in comparison with the “Hot†group. The distinct immune cell content of both groups was confirmed by quantitative immunostainings. Get Set Enrichment Analysis showed that the “Cold†group had upregulated NOTCH pathway and mainly oligodendrocyte precursor cell and neuronal phenotypes while the “Hot†group exhibited predominantly astrocytic and neural stem cell phenotypes. In silico deconvolution identified the cerebellar granule cell lineage as a putative origin and as the cell context to understand the effects of genetic alterations and NOTCH signaling.
Histological diagnosis of rosette-forming tumors encompasses heterogeneous tumor entities. Our study identified distinct tumor cell contexts and microenvironments as key features to better understand and manage these neoplasms.EGA study EGAS00001006502