Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker

Abstract

Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients' clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: "TCL1 MBEN" and "TCL2 MBEN" which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable "TCL1 MBEN" subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable "TCL2 MBEN" subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. "TCL2 MBEN" also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.

Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation

“…DNA methylation, targeted next-generation sequencing (NGS) and RNA sequencing DNA (84) and RNA (53) were extracted from formalinfixed and paraffin-embedded (FFPE) target tumor tissue samples using the automated Maxwell system (Promega, Madison, WI, USA) [15,16]. DNA was analyzed using the Illumina Human Methylation 450 k or 850 k/EPIC BeadChip array as described [5,6,14,16,22,23].…”

“…Sequence data were mapped to the reference human genome using the Burrows-Wheeler Aligner and were processed using the publicly available SAM tools. RNA sequencing of 53 samples was performed on a NextSeq 500 (Illumina) as previously described [15,26]. The reads alignments and identification of low-quality or outlier samples was performed as described [15,20].…”

“…RNA sequencing of 53 samples was performed on a NextSeq 500 (Illumina) as previously described [15,26]. The reads alignments and identification of low-quality or outlier samples was performed as described [15,20]. Unsupervised tumor samples comparison was performed with hierarchical clustering, principal component analysis, t-SNE analysis, and based on the selection of the top 250, 500 and 1000 most variable genes with log2 RPKM gene expression normalization.…”

“…Unsupervised tumor samples comparison was performed with hierarchical clustering, principal component analysis, t-SNE analysis, and based on the selection of the top 250, 500 and 1000 most variable genes with log2 RPKM gene expression normalization. Differential gene expression analysis was performed by comparing one molecular group against the others using DESeq 2 R package (adjusted p < 0•05) and gene ontology analysis was done using ClueGO (Cytoscape version 3.4) [4,15]. Fusion discovery was done based on RNA sequencing data using five independent algorithms [20,26].…”

<p>Baohuoside I via mTOR Apoptotic Signaling to Inhibit Glioma Cell Growth</p>

“…In neuroepithelial tissue tumors, the incidence of glioma is about 50%. 1 The high proliferation and invasive behavior of glioma is a difficult treatment problem today, it can effectively "escape" from surgery, radiotherapy, chemotherapy, immunotherapy and other programs, resulting in the ultimate death of patients. 2 At present, microsurgery can only cut the tumors that are visible to the naked eye, while many "root-like" growths of glioma cells infiltrate into normal brain tissue.…”