Dataset Information

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.

SUBMITTER: Sievers P

PROVIDER: S-EPMC8500895 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Sievers Philipp P Henneken Sophie C SC Blume Christina C Sill Martin M Schrimpf Daniel D Stichel Damian D Okonechnikov Konstantin K Reuss David E DE Benzel Julia J Maaß Kendra K KK Kool Marcel M Sturm Dominik D Zheng Tuyu T Ghasemi David R DR Kohlhof-Meinecke Patricia P Cruz Ofelia O Suñol Mariona M Lavarino Cinzia C Ruf Viktoria V Boldt Henning B HB Pagès Mélanie M Pouget Celso C Schweizer Leonille L Kranendonk Mariëtte E G MEG Akhtar Noreen N Bunkowski Stephanie S Stadelmann Christine C Schüller Ulrich U Mueller Wolf C WC Dohmen Hildegard H Acker Till T Harter Patrick N PN Mawrin Christian C Beschorner Rudi R Brandner Sebastian S Snuderl Matija M Abdullaev Zied Z Aldape Kenneth K Gilbert Mark R MR Armstrong Terri S TS Ellison David W DW Capper David D Ichimura Koichi K Reifenberger Guido G Grundy Richard G RG Jabado Nada N Krskova Lenka L Zapotocky Michal M Vicha Ales A Varlet Pascale P Wesseling Pieter P Rutkowski Stefan S Korshunov Andrey A Wick Wolfgang W Pfister Stefan M SM Jones David T W DTW von Deimling Andreas A Pajtler Kristian W KW Sahm Felix F

Acta neuropathologica 20210805 5

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 separa ...[more]

PMID: 34355256

Similar Datasets

Project description:Neuroepithelial tumors with fusion of PLAGL1 or amplification of PLAGL1/PLAGL2 have recently been described often with ependymoma-like or embryonal histology respectively. To further evaluate emerging entities with PLAG-family genetic alterations, the histologic, molecular, clinical, and imaging features are described for 8 clinical cases encountered at St. Jude (EWSR1-PLAGL1 fusion n = 6; PLAGL1 amplification n = 1; PLAGL2 amplification n = 1). A histologic feature observed on initial resection in a subset (4/6) of supratentorial neuroepithelial tumors with EWSR1-PLAGL1 rearrangement was the presence of concurrent ependymal and ganglionic differentiation. This ranged from prominent clusters of ganglion cells within ependymoma/subependymoma-like areas, to interspersed ganglion cells of low to moderate frequency among otherwise ependymal-like histology, or focal areas with a ganglion cell component. When present, the combination of ependymal-like and ganglionic features within a supratentorial neuroepithelial tumor may raise consideration for an EWSR1-PLAGL1 fusion, and prompt initiation of appropriate molecular testing such as RNA sequencing and methylation profiling. One of the EWSR1-PLAGL1 fusion cases showed subclonal INI1 loss in a region containing small clusters of rhabdoid/embryonal cells, and developed a prominent ganglion cell component on recurrence. As such, EWSR1-PLAGL1 neuroepithelial tumors are a tumor type in which acquired inactivation of SMARCB1 and development of AT/RT features may occur and lead to clinical progression. In contrast, the PLAGL2 and PLAGL1 amplified cases showed either embryonal histology or contained an embryonal component with a significant degree of desmin staining, which could also serve to raise consideration for a PLAG entity when present. Continued compilation of associated clinical data and histopathologic findings will be critical for understanding emerging entities with PLAG-family genetic alterations.

Project description:The family of pediatric fibroblastic and myofibroblastic proliferations encompasses a wide spectrum of pathologic entities with overlapping morphologies and ill-defined genetic abnormalities. Among the superficial lesions, lipofibromatosis (LPF), composed of an admixture of adipose tissue and fibroblastic elements, in the past has been variously classified as infantile fibromatosis or fibrous hamartoma of infancy. In this regard, we have encountered a group of superficial soft tissue tumors occurring in children and young adults, with a notably infiltrative growth pattern reminiscent of LPF, variable cytologic atypia, and a distinct immunoprofile of S100 protein and CD34 reactivity, suggestive of neural differentiation. SOX10 and melanocytic markers were negative in all cases tested. In contrast, a control group of classic LPF displayed bland, monomorphic histology and lacked S100 protein immunoreactivity. To define the pathogenetic abnormalities in these seemingly distinctive groups, we performed RNA sequencing for fusion gene discovery in 2 cases each, followed by screening for any novel alterations identified in a larger cohort representing both entities. The 2 index LPF-like neural tumors (LPF-NT) showed TPR-NTRK1 and TPM3-NTRK1 gene fusions, which were further validated by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction. Subsequent FISH screening of 14 LPF-NT identified recurrent NTRK1 gene rearrangements in 10 (71%) cases. Of the NTRK1-negative LPF-NT cases, 1 case each showed ROS1 and ALK gene rearrangements. In contrast, none of the 25 classic LPFs showed NTRK1 gene rearrangements, although regional abnormalities were noted in the 1q21-22 region by FISH in a majority of cases. Furthermore, NTRK1 immunostaining was positive only in NTRK1-rearranged S100-positive LPF-NT but negative in classic LPF. These results suggest that NTRK1 oncogenic activation through gene fusion defines a novel and distinct subset of soft tissue tumors resembling LPF, but displaying cytologic atypia and a neural immunophenotype, provisionally named LPF-like neural tumors.

Project description:Infantile fibrosarcomas (IFS) represent a distinct group of soft tissue tumors occurring in patients under 2 years of age and most commonly involving the extremities. Most IFS show recurrent ETV6-NTRK3 gene fusions, sensitivity to chemotherapy, and an overall favorable clinical outcome. However, outside these well-defined pathologic features, no studies have investigated IFS lacking ETV6-NTRK3 fusions, or tumors with the morphology resembling IFS in older children. This study was triggered by the identification of a novel SEPT7-BRAF fusion in an unclassified retroperitoneal spindle cell sarcoma in a 16-year-old female by targeted RNA sequencing. Fluorescence in situ hybridization screening of 9 additional tumors with similar phenotype and lacking ETV6-NTRK3 identified 4 additional cases with BRAF gene rearrangements in the pelvic cavity (n=2), paraspinal region (n=1), and thigh (n=1) of young children (0 to 3 y old). Histologically, 4 cases including the index case shared a fascicular growth of packed monomorphic spindle cells, with uniform nuclei and fine chromatin, and a dilated branching vasculature; while the remaining case was composed of compact cellular sheets of short spindle to ovoid cells. In addition, a minor small blue round cell component was present in 1 case. Mitotic activity ranged from 1 to 9/10 high power fields. Immunohistochemical stains were nonspecific, with only focal smooth muscle actin staining demonstrated in 3 cases tested. Of the remaining 5 BRAF negative cases, further RNA sequencing identified 1 case with EML4-NTRK3 in an 1-year-old boy with a foot IFS, and a second case with TPM3-NTRK1 fusion in a 7-week-old infant with a retroperitoneal lesion. Our findings of recurrent BRAF gene rearrangements in tumors showing morphologic overlap with IFS expand the genetic spectrum of fusion-positive spindle cell sarcomas, to include unusual presentations, such as older children and adolescents and predilection for axial location, thereby opening new opportunities for kinase-targeted therapeutic intervention.

Project description:Giant cell tumors of soft tissue (GCT-ST) are rare low-grade neoplasms that were at one time thought to represent the soft tissue counterparts of GCT of bone (GCT-B) but are now known to lack the H3F3 mutations characteristic of osseous GCT. We present six distinctive giant cell-rich soft tissue neoplasms that expressed keratins and carried a recurrent HMGA2-NCOR2 gene fusion. Patients were five females and one male aged 14-60 years (median, 29). All presented with superficial (subcutaneous) masses that were removed by conservative marginal (3) or wide (2) local excision. The tumors originated in the upper extremity (2), lower extremity (2), head/neck (1), and trunk (1). Five patients with follow-up (median, 21 months; range, 14-168) remained disease-free. Grossly, all tumors were well-demarcated but not encapsulated with variable lobulation. Histologically, they were composed of bland plump epithelioid or ovoid to spindled mononuclear cells admixed with evenly distributed multinucleated osteoclast-type giant cells. Foci of stromal hemorrhage and hemosiderin were seen in all cases. The mitotic activity ranged from 2 to 14/10 high power fields (median: 10). Foci of necrosis and vascular invasion were seen in one case each. The mononuclear cells were immunoreactive with the AE1/AE3 keratin cocktail and less frequently/less diffusely for K7 and K19 but lacked expression of other lineage-associated markers. RNA-based next-generation sequencing revealed an HMGA2-NCOR2 fusion in all tumors. None of the keratin-negative conventional GCT-ST showed the HMGA2-NCOR2 fusion (0/7). Metaplastic bone (4/9) and SATB2 expression (3/4) were frequent in keratin-negative conventional GCT-ST but were lacking in keratin-positive HMGA2-NCOR2 fusion-positive tumors. The distinctive immunophenotype and genotype of these tumors strongly suggest that they represent a discrete entity, differing from conventional GCT-ST and other osteoclast-rich morphologic mimics. Their natural history appears favorable, although a study of additional cases and longer follow-up are warranted.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets