Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors

Abstract

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

The oncogenic fusion landscape in pediatric CNS neoplasms

“…However, they also occur in embryonal tumors (2%; 1/53), sarcomas (9%; 5/53) and other CNS tumor diagnoses (17%; 9/53). They cover a variety of fusion partners, including recurrent partners such as EWS RNA binding protein 1 (EWSR1), MYB proto-oncogene, transcription factor (MYB), and zinc finger translocation associated ( ZFTA , formerly C11orf95 ) [ 15 , 27 , 33 , 105 , 132 , 176 , 207 , 226 , 245 , 255 ]. Instead of harboring kinase domains, these fusions are mostly characterized by transcription factors and partners with a DNA binding domain, indicating that besides kinases, these are important partners in oncogenic fusions in pediatric CNS tumors.…”

Methylation classifiers: Brain tumors, sarcomas, and what's next

“…However, a considerable number refer to novel tumor entities, some of which already will be included in the fifth edition of the WHO classification of tumors of the CNS. These include the “infant type hemispheric glioma” previously diagnosed as glioblastoma in most instances or the “diffuse glioneuronal tumor with oligodendroglioma‐like features and nuclear clusters (DGONC),” 69 Novel tumors not yet included are the “PLAGL1‐fused neuroepithelial tumor” 70 reminiscent of ependymoma or the “Primary mismatch repair deficient IDH‐mutant astrocytoma (PMMRDIA).” 71 Characterization of several other novel tumor types can be expected within short time. Recently, methylation analysis has been employed to characterize hamartous malformations and cortical dysplasias, both constituting challenging differential diagnoses to low glioneuronal tumors 72,73 …”

Molecular Stratification of Childhood Ependymomas as a Basis for Personalized Diagnostics and Treatment

“…Tumors with neither ZFTA nor YAP1 alterations are considered as a separate group, and recent findings emphasize the need for a finer specification. A distinct entity is formed by PLAGL1 rearranged EPNs, harboring EWSR1-PLAGL1 and less commonly PLAGL1-FOXO1 or PLAGL1-EP300 fusions [39], which echoes molecular landscapes of soft tissue sarcomas and a group of rare mesenchymal (non-meningothelial) and glioneuronal CNS tumors with EWSR1-non-ETS fusions [40,41]. Nevertheless, for the vast majority of ST-EPNs lacking recurrent chromosomal rearrangements, the oncogenic driver events remain elusive.…”