Embryonal tumors with multi-layered rosettes: a disease of dysregulated miRNAs
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TOPIC REVIEW
Embryonal tumors with multi-layered rosettes: a disease of dysregulated miRNAs Nikhil Raghuram1 · Sara Khan2,3 · Iqra Mumal3,4 · Eric Bouffet1 · Annie Huang1,3,4,5 Received: 3 August 2020 / Accepted: 23 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Introduction ETMRs are highly lethal, pediatric embryonal brain tumors, previously classified as various histologic diagnoses including supratentorial primitive neuroectodermal tumors (sPNET) and CNS PNET. With recognition that these tumors harbor recurrent amplification of a novel oncogenic miRNA cluster on chr19, C19MC, ETMRs were designated as a distinct biological and molecular entity with a spectrum of histologic and clinical manifestations. Methods We reviewed published literature describing clinical presentation, the genetic and epigenetic drivers of oncogenesis, and recent therapeutic strategies adopted to combat these aggressive tumors. Results As a consequence of C19MC amplification, ETMRs upregulate several oncogenic and pluripotency proteins, including LIN28A, DNMT3B and MYCN, that confer a unique epigenetic signature reminiscent of nascent embryonic stem cells. In this review, we focus on the dysregulation of miRNAs in ETMR, the major pathogenic mechanism identified in this disease. Conclusion Despite the use of multi-modal therapeutic regimens, ETMR patients have dismal survival. Understanding the unique biology of these tumors has provided new insights towards novel therapeutic targets. Keywords ETMR · C19MC · LIN28 · Embryonal tumors
Introduction
* Annie Huang [email protected] 1
Division of Hematology‑Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON M5G1X8, Canada
2
Monash Children’s Cancer Centre, Monash Children’s Hospital. Monash Health. Center for Cancer Research, Hudson Institute of Medical Research, and Department of Molecular and Translational Science, School of Medicine, Nursing and Health Science, Monash University, Clayton, VIC 3168, Australia
3
Division of Hematology/Oncology, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON M5G0A4, Canada
4
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S1A8, Canada
5
Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON M5G1L7, Canada
ETMRs (Embryonal Tumors with Multi-layered Rosettes) are a recently described, highly aggressive, and poorly understood category of embryonal brain tumors (EBT) predominantly affecting young children [1]. Based on unique histologic features, embryonal tumors with abundant neuropil and true rosettes (ETANTR) were first described as a new category of aggressive embryonal tumors [1]. However, large scale multi-omics studies on EBTs showed that ETANTR, and a subset of other embryonal tumors, including ependymoblastoma, medulloepithelioma and supratentorial primitive ne
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