Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification

Abstract

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0–14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

A comprehensive analysis of infantile central nervous system tumors to improve distinctive criteria for infant‐type hemispheric glioma versus desmoplastic infantile ganglioglioma/astrocytoma

“…In the CNS, gains and amplifications of these genes have also been reported in gliomas, and it has been evidenced that PLAGL2 promotes renewal of neural stem cells/ progenitor cells by inhibiting their differentiation and thus promoting gliomagenesis [31]. Similarly to the two specimens in the current study, the reported cases with PLAGL2 amplification mainly affected infants and were supratentorial [28,32]. This case and ours presented an amplification of the PLAGL2 gene.…”

“…Radiologically, they appear as a solid and cystic peri-or intraventricular mass with an intermediate restriction of the diffusion, high perfusion value, and an intense enhancement following gadolinium injection. Histopathologically, the tumors are well-circumscribed with a branching capillary network, but without microvascular proliferation, as previously described [28]. The tumor cells are monotonous without a distinct pattern of differentiation.…”

An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma

“…Recently, a subset of embryonal brain tumors was found to be defined by amplification and overexpression of PLAGL2, and our study expands on its oncogenic importance [73].…”

“…Recently, a subset of embryonal brain tumors was found to be defined by amplification and overexpression of PLAGL2 , and our study expands on its oncogenic importance [73]. PLAGL2 was initially described as a homolog of the PLAG1 transcription factor, whose translocation-driven overexpression defines pleomorphic adenoma of the salivary glands [74].…”

Ultra-fast deep-learned pediatric CNS tumor classification during surgery

“…2021), sometimes classified by sturgeon as a SUBEPN. PMC_88; low grade glioma with a PLAG amplification (Keck et al . 2022), Sturgeon does not reach the 0.8 threshold in this sample, but we note that the highest scoring class is often Medulloblastoma Group 3.…”