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  • KSBNS 2024

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Original Article

Exp Neurobiol 2023; 32(5): 354-361

Published online October 31, 2023

https://doi.org/10.5607/en23021

© The Korean Society for Brain and Neural Sciences

Methylation-based Subclassifications of Embryonal Tumor with Multilayered Rosettes in Not Just Pediatric Brains

Eric Eunshik Kim1, Kwanghoon Lee1, Ji-Hoon Phi2, Min-Sung Kim2, Hyoung Jin Kang3,4, Hongseok Yun5 and Sung-Hye Park1,6*

1Department of Pathology, College of Medicine, Seoul National University, Seoul 03080, 2Department of Neurosurgery, College of Medicine, Seoul National University, Seoul 03080, 3Department of Pediatrics, College of Medicine, Seoul National University, Seoul 03080, 4Cancer Research Institute, Seoul National University Children's Hospital, Seoul 03080, 5Department of Genomic Medicine, College of Medicine, Seoul National University Hospital, Seoul 03080, 6Institute of Neuroscience, College of Medicine, Seoul National University, Seoul 03080, Korea

Correspondence to: *To whom correspondence should be addressed.
TEL: 82-2-2072-3090, FAX: 82-2-743-5530
e-mail: shparknp@snu.ac.kr

Received: July 13, 2023; Revised: September 23, 2023; Accepted: October 16, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The aim of this study is to investigate the genetic profiles and methylation-based classifications of Embryonal tumor with multilayered rosettes (ETMR), with a specific focus on differentiating between C19MC amplified and C19MC-not amplified groups, including cases with DICER1 mutations. To achieve this, next-generation sequencing using a targeted gene panel for brain tumors and methylation class studies using the Epic850K microarray were performed to identify tumor subclasses and their clinicopathological characteristics. The study cohort consisted of four patients, including 3 children (a 4-months/F, a 9-months/M, and a 2 y/F), and one adult (a 30 y/Male). All three tumors in the pediatric patients originated in the posterior fossa and exhibited TTYH1:C19MC fusion and C19MC amplification. The fourth case in the adult patient involved the cerebellopontine angle with biallelic DICER1 mutation. Histopathological examination revealed typical embryonal features characterized by multilayered rosettes and abundant neuropils in all cases, while the DICER1-mutant ETMR also displayed cartilage islands in addition to the classic ETMR pathology. All four tumors showed positive staining for LIN28A. The t-SNE clustering analysis demonstrated that the first three cases clustered with known subtypes of ETMR, specifically C19MC amplified, while the fourth case clustered separately to non-C19MC amplified subclass. During the follow-up period of 6~12 months, leptomeningeal dissemination of the tumor occurred in all patients. Considering the older age of onset in DICER1-mutant ETMR, genetic counseling should be recommended due to the association of DICER1 mutations with germline and second-hit somatic mutations in cancer.

Graphical Abstract


Keywords: Brain neoplasm, Cerebral primitive neuroectodermal tumor, DNA methylation, DICER1