DICER1-associated metastatic abdominopelvic primitive neuroectodermal tumor with an EWSR1 rearrangement in a 16-yr-old female.

C O L D S P R I N G H A R B O R Molecular Case Studies | RESEARCH REPORT DICER1-associated metastatic abdominopelvic primitive neuroectodermal tumor with an EWSR1 rearrangement in a 16-yr-old female Alessia Pancaldi,1,8 Lei Peng,2,8 Daniel S. Rhee,2,3 Emily Dunn,4 Jessica A. Forcucci,5,7 Deborah Belchis,5,6 and Christine A. Pratilas2 1 Post Graduate School of Pediatrics, Department of Medical and Surgical Sciences of the Mothers, Children and Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; 2Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA; 3 Division of Pediatric Surgery, Department of Surgery, 4Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; 5Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland 21287, USA; 6Doctor’s Community Hospital, Lanham, Maryland 20706, USA Corresponding author: © 2020 Pancaldi et al. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited. Ontology terms: Ewing’s sarcoma; multinodular goiter; neoplasm of the genitourinary tract Published by Cold Spring Harbor Laboratory Press doi:10.1101/mcs.a005603 Abstract We report a case of a DICER1-associated EWSR1-rearranged malignant primitive neuroectodermal tumor (PNET) arising in a patient with DICER1 tumor predisposition syndrome. A 16-yr-old female with a history of multinodular goiter presented with a widely metastatic abdominal small round blue cell tumor with neuroectodermal differentiation. EWSR1 gene rearrangement was identified in the tumor by fluorescence in situ hybridization (FISH). Genetic analysis revealed biallelic pathogenic DICER1 variation. The patient was treated with an aggressive course of chemotherapy, surgery, and radiation with complete pathologic response. We believe this case to represent a new expression of the DICER1 tumor predisposition syndrome, an entity caused by deleterious germline mutations in the DICER1 gene, encoding a ribonuclease active in the processing of miRNA. Patients with germline mutations in DICER1 develop a diverse group of benign and malignant tumors. Some of these tumors have been noted to have immature neuroepithelium as a component, including the ciliary body medulloepithelioma and the recently described DICER1-associated presacral malignant teratoid neoplasm. To our knowledge, abdominal sarcomas that resemble PNET histology with an EWSR1 rearrangement have not previously been described as a classical expression of the DICER1 syndrome phenotype. [Supplemental material is available for this article.] INTRODUCTION DICER1 syndrome is an autosomal dominant hereditary tumor predisposition syndrome caused by deleterious germline mutations of the DICER1 gene (Warren et al. 2020). The DICER1 gene is located on Chromosome 14 and encodes a RNase III endoribonuclease that processes precursor micro RNAs (miRNAs) into functional mature miRNAs, which serve 7 Present address: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA 8 These authors contributed equally to this work. Cite this article as Pancaldi et al. 2020 Cold Spring Harb Mol Case Stud 6: a005603 1 of 11 C O L D S P R I N G H A R B O R Molecular Case Studies EWSR1-rearranged metastatic PNET in DICER1 syndrome to negatively regulate gene expression by messenger RNA (mRNA) silencing or repressing translation (Foulkes et al. 2014; Wormald et al. 2018). The predicted effects of mutations in DICER1 include reduction of DICER1 protein level, consequently reduction of miRNA levels, and thereby reduction in tumor-suppression activity. DICER1 function in cancer, however, may vary, as its inactivation has been associated with tumorigenesis in some tumor types, whereas increased DICER1 protein expression has been associated with invasion and metastasis in others (Kumar et al. 2007; Hata and Kashima 2016). The expression of DICER1 can be increased or decreased in various types of cancers, leading to expression changes in the large number of cellular miRNAs. Instances of global down-regulation of miRNAs in tumors have been reported, especially in poorly differentiated ones, and one explanation proposed is that the function of miRNAs is to define lineage-specific properties so that a low abundance of miRNAs could promote the undifferentiated state of tumor cells (Lu et al. 2005; Hata and Kashima 2016). On the other hand, elevated levels of DICER1 have been found in tumor cells, even if global up-regulation of miRNA is uncommon (Hata and Kashima 2016). DICER1-associated tumors appear to arise as a result of the second hit hypothesis, whereby, in addition to a heterozygous germline mutation, typically a truncating loss of function mutation, a second, tumor-specific missense mutation occurs (Schultz 2018; Wormald et al. 2018). These somatic missense mutations predominantly occur within exons 24 and 25 in the RNaseIIIb domain at one of five hotspot codons, E105, D1709, G1809, D1810, or E1813 (Pugh et al. 2014). Initially described in familial pleuropulmonary blastoma (Hill et al. 2009; Slade et al. 2011), in which 70% of cases harbor a germline heterozygous DICER1 loss-of-function mutation, DICER1 syndrome has since been associated with a variety of additional benign and malignant conditions including lung cysts, cystic nephroma (Bahubeshi et al. 2010; Faure et al. 2016), Wilms tumor (Foulkes et al. 2014), multinodular goiter (Rio Frio et al. 2011; Schultz 2018), thyroid adenoma, juvenile-type intestinal polyps, ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, pituitary blastoma, pinealoblastoma (Schultz 2018), cervical embryonal rhabdomyosarcoma (Doros et al. 2012), Sertoli–Leydig tumors (Fremerey et al. 2017), and malignant sacrococcygeal tumors (Nakano et al. 2019; Warren et al. 2020). DICER1 syndrome exhibits incomplete penetrance, and up to 95% of DICER1 carriers do not develop any significant clinical features by the age of 10 (Doros et al. 1993; Wormald et al. 2018; de Kock et al. 2019; Stewart et al. 2019). Although embryonal rhabdomyosarcomas and renal sarcomas are recognized in association with DICER1 syndrome, and recent reports have identified a small cohort of patients with intracranial sarcomas, other sarcoma types are not known to occur in these patients. Here, we report the unique case of a teenage girl who presented with a large abdominopelvic malignancy that was identified as a DICER1-associated, EWSR1-rearranged primitive neuroectodermal tumor (PNET), and thereby adds to the spectrum of malignant tumors that occur in patients with this cancer predisposition syndrome. RES (...truncated)