The oncogenic fusion landscape in pediatric CNS neoplasms

Abstract

Pediatric neoplasms in the central nervous system (CNS) are the leading cause of cancer-related deaths in children. Recent developments in molecular analyses have greatly contributed to a more accurate diagnosis and risk stratification of CNS tumors. Additionally, sequencing studies have identified various, often entity specific, tumor-driving events. In contrast to adult tumors, which often harbor multiple mutated oncogenic drivers, the number of mutated genes in pediatric cancers is much lower and many tumors can have a single oncogenic driver. Moreover, in children, much more than in adults, fusion proteins play an important role in driving tumorigenesis, and many different fusions have been identified as potential driver events in pediatric CNS neoplasms. However, a comprehensive overview of all the different reported oncogenic fusion proteins in pediatric CNS neoplasms is still lacking. A better understanding of the fusion proteins detected in these tumors and of the molecular mechanisms how these proteins drive tumorigenesis, could improve diagnosis and further benefit translational research into targeted therapies necessary to treat these distinct entities. In this review, we discuss the different oncogenic fusions reported in pediatric CNS neoplasms and their structure to create an overview of the variety of oncogenic fusion proteins to date, the tumor entities they occur in and their proposed mode of action.

Keywords: Brain tumor; Kinase; Oncogenic fusion protein; Pediatric CNS tumors; Transcription factor.

Fig. 1

Characteristics of fusion proteins observed in pediatric brain tumors. a Complete fusion partner network in pediatric CNS neoplasms. Green = N terminal partner, red = C terminal partner. Multiple connecting lines indicate that fusions were identified in multiple tumor types. b The majority (73/110) of fusions have been observed in a single tumor type. 37/110 fusions have been detected in two or more tumor types. The tumor types are annotated as mentioned in the original publication, it might be possible that some tumor types have been wrongly diagnosed or that diagnosis was changed after this publication. This is not considered. c The majority (152/171) of the pediatric CNS tumors with fusions present are glial tumors. d Based on WHO classification there are slightly more pediatric CNS low grade (LG) tumors than high grade (HG) tumors with driving fusion proteins. The WHO classification is based on the original publication and/or the tumor type. e Fusions in pediatric CNS tumors are slightly more often the results of inter-chromosomal rearrangements than intra-chromosomal rearrangements. f Most of the fusion proteins have at least one partner that functions as a kinase. Most other fusions have at least one transcription factor

Fig. 2

Fusion proteins are most common in the RAS/MAPK pathway. a Schematic representation of the RAS/MAPK, PI3K/AKT/mTOR and JAK/STAT pathway. Kinases implicated in fusions in pediatric CNS tumors are marked with a red dashed circle. Created with BioRender.com b Five common trends in fusion proteins observed in pediatric CNS tumors. I. C-terminal kinase protein fused to a protein with dimerization domains. II. C-terminal kinase protein fused to a protein that is highly expressed in the CNS. III. N-terminal kinase protein fused to a protein with dimerization domains. IV. Transcription factors with a transcription activation domain fused to proteins with a DNA binding domain. V. C-terminal transcription factors with a transcription activation domain and a DNA binding domain fused to a protein with no clear functional domains. c Examples of oncogenic fusions in pediatric CNS tumors that belong to the five different fusions types as mentioned in b. For every protein, the exons that are retained in the fusion protein are specified, as well as the total exons (in between brackets) in the original protein

Fig. 3

Characteristics of kinase fusions in pediatric CNS neoplasms a Eight kinase families are responsible for all kinase fusions that are mainly present in glial tumors. b Kinase proteins are not limited to one pediatric CNS tumor type but are present in multiple different tumor types. Graphs made by https://app.rawgraphs.io. AA anaplastic astrocytoma, DA diffuse astrocytoma, DIPG diffuse intrinsic pontine glioma, DLGT diffuse leptomeningeal glioneural tumor, DNET dysembryoplastic neuroepithelial tumor, DOD diffuse oligodendroglioma, EPN ependymoma, FSCN fibroblastic spindle cell neoplasm, GBM glioblastoma, GNT glial neuronal tumor, CNS-GNB central nervous system ganglioneuroblastoma, HGG high grade glioma, IHG interhemiscpheric glioma, IMT inflammatory myofibroblastic tumor nervous system—ganglioneuroblastoma, LGG low grade glioma, MNG meningioma, NBS-HGG non brain stem high grade glioma, NET neural epithelial tumor, OA oligoastrocytoma, OD oligodendroglioma, PA pilocytic astrocytoma, GG ganglioglioma, PGNT papillary glial neuronal tumor, PLNTY polymorphous neuro-epithelial tumor of the young, PXA pleomorphic xanthoastrocytoma

Fig. 4

Characteristics of transcription regulator fusions in pediatric CNS neoplasms a Nine transcription factors are responsible for most transcription factor fusions that are mainly present in glial tumors. b Kinase proteins are not limited to one pediatric CNS tumor type but are present in multiple different tumor types. Graph made by https://app.rawgraphs.io. AB astroblastoma, AFH angiomatoid fibrous histiocytoma, AG angiocentric glioma, APA anaplastic pleomorphic astrocytoma, AO anaplastic oligodendroglioma, CNS EFT–CIC central nervous system Ewing Sarcoma Family Tumor with CIC alteration, CNS—ET central nervous system embryonal tumor, CNS-HGNET MN1 central nervous system high grade neuroepithelial tumor with MN1 alteration, DA diffuse astrocytoma, DSRCT desmoplastic small round cell tumor, ELTMD ependymoma like tumor with mesenchymal differentiation, EPN ependymoma, GBM glioblastoma, GG ganglioglioma, GNT glial neuronal tumor, HPC hemangiopericytoma, IHG interhemiscpheric glioma, IMMT intracranial myxoid mesenchymal tumor, IRMS intracranial rhabdomyosarcoma, MNG meningioma, NF neurofibroma, OD oligodendroglioma, PA pilocytic astrocytoma, PESS primary epidural spinal sarcoma, PNET primitive neuroectodermal tumor, SFT solitary fibrous tumor