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

Abstract

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly malignant neoplasms posing diagnostic challenge due to a lack of defining molecular markers. CNS neuroblastoma with forkhead box R2 (FOXR2) activation (CNS_NBL) emerged as a distinct pediatric brain tumor entity from a pool previously diagnosed as primitive neuroectodermal tumors of the central nervous system (CNS-PNETs). Current standard of identifying CNS_NBL relies on molecular analysis. We set out to establish immunohistochemical markers allowing safely distinguishing CNS_NBL from morphological mimics. To this aim we analyzed a series of 84 brain tumors institutionally diagnosed as CNS-PNET. As expected, epigenetic analysis revealed different methylation groups corresponding to the (1) CNS-NBL (24%), (2) glioblastoma IDH wild-type subclass H3.3 G34 (26%), (3) glioblastoma IDH wild-type subclass MYCN (21%) and (4) ependymoma with RELA_C11orf95 fusion (29%) entities. Transcriptome analysis of this series revealed a set of differentially expressed genes distinguishing CNS_NBL from its mimics. Based on RNA-sequencing data we established SOX10 and ANKRD55 expression as genes discriminating CNS_NBL from other tumors exhibiting CNS-PNET. Immunohistochemical detection of combined expression of SOX10 and ANKRD55 clearly identifies CNS_NBL discriminating them to other hemispheric CNS neoplasms harboring "PNET-like" microscopic appearance. Owing the rarity of CNS_NBL, a confirmation of the elaborated diagnostic IHC algorithm will be necessary in prospective patient series.

• Authors: Andrey Korshunov, Konstantin Okonechnikov, Felix Schmitt-Hoffner, Marina Ryzhova, Felix Sahm, Damian Stichel, Daniel Schrimpf, David E Reuss, Philipp Sievers, Abigail Kora Suwala, Ella Kumirova, Olga Zheludkova, Andrey Golanov, David T W Jones, Stefan M Pfister, Marcel Kool, Andreas von Deimling
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 9 Issue 1 Pg. 20 (02 03 2021) ISSN: 2051-5960 [Electronic] England
• PMID: 33536079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ANKRD55 protein, human
• Biomarkers, Tumor
• Carrier Proteins
• FOXR2 protein, human
• Forkhead Transcription Factors
• SOX10 protein, human
• SOXE Transcription Factors

Topics

• Adolescent
• Biomarkers, Tumor (genetics)
• Carrier Proteins (genetics)
• Central Nervous System Neoplasms (classification, diagnosis, genetics, pathology)
• Child
• Child, Preschool
• DNA Methylation (genetics)
• Female
• Forkhead Transcription Factors (genetics)
• Gene Expression Profiling
• Humans
• Immunohistochemistry
• Male
• Neuroblastoma (diagnosis, genetics, pathology)
• Neuroectodermal Tumors, Primitive (classification, diagnosis, genetics, pathology)
• SOXE Transcription Factors (genetics)