GOPC-ROS1 Fusion Due to Microdeletion at 6Q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas And

J Neuropathol Exp Neurol Vol. 78, No. 12, December 2019, pp. 1089–1099 doi: 10.1093/jnen/nlz093 ORIGINAL ARTICLE GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors Downloaded from https://academic.oup.com/jnen/article/78/12/1089/5593615 by New York University user on 25 August 2020 Timothy E. Richardson, DO, PhD, Karen Tang, MD, Varshini Vasudevaraja, MS, Jonathan Serrano, BS, Christopher M. William, MD, PhD, Kanish Mirchia, MD, Christopher R. Pierson, MD, PhD, Jeffrey R. Leonard, MD, Mohamed S. AbdelBaki, MD, Kathleen M. Schieffer, PhD, Catherine E. Cottrell, PhD, Zulma Tovar-Spinoza, MD, Melanie A. Comito, MD, Daniel R. Boue, MD, PhD, George Jour, MD, and Matija Snuderl, MD features; the third tumor aligned best with glioblastoma and Abstract showed no evidence of neuronal differentiation. Copy number ROS1 is a transmembrane receptor tyrosine kinase proto- profiling revealed chromosome 6q22 microdeletions correspond- oncogene that has been shown to have rearrangements with sev- ingtotheGOPC-ROS1 fusion in all 3 cases and methylation pro- eral genes in glioblastoma and other neoplasms, including intra- filing showed that the tumors did not cluster together as a single chromosomal fusion with GOPC due to microdeletions at 6q22.1. entity or within known methylation classes by t-Distributed Sto- ROS1 fusion events are important findings in these tumors, as chastic Neighbor Embedding. they are potentially targetable alterations with newer tyrosine kinase inhibitors; however, whether these tumors represent a dis- Key Words: 6q22, Astrocytoma, Brain tumor, GOPC, Pediatric gli- tinct entity remains unknown. In this report, we identify 3 cases oma, ROS1. of unusual pediatric glioma with GOPC-ROS1 fusion. We reviewed the clinical history, radiologic and histologic features, performed methylation analysis, whole genome copy number profiling, and next generation sequencing analysis for the detec- INTRODUCTION tion of oncogenic mutation and fusion events to fully characterize ROS1, located at 6q22.1, encodes a transmembrane re- the genetic and epigenetic alterations present in these tumors. ceptor tyrosine kinase that under normal circumstances binds Two of 3 tumors showed pilocytic features with focal expression to growth factors and undergoes dimerization and phosphory- of synaptophysin staining and variable high-grade histologic lation with transmission of growth signals downstream through intracellular second messenger systems (1). Onco- genic ROS1 fusion was originally discovered in a glioblas- From the Department of Pathology, State University of New York, Upstate toma (GBM) cell line (U118MG) in the late 1980s (2–4). Medical University, Syracuse, New York (TER, KM); Department of Pe- Subsequent work demonstrated this original alteration to be diatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New due to an intrachromosomal microdeletion of 240–250 kilo- York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children’s Hospital and bases (kb), resulting in fusion of GOPC and ROS1 in this The Ohio State University (CRP, CEC, DRB); Department of Neurologi- cell line (5). cal Surgery, Nationwide Children’s Hospital (JRL); Department of He- This del(6)(q22;q22) and the resulting rearrangement matology, Oncology, and Bone Marrow Transplant, Nationwide produces a constitutively active tyrosine kinase fusion prod- Children’s Hospital and The Ohio State University (MSA); Nationwide uct that has been demonstrated to be sufficient to produce Children’s Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of neoplastic transformation and tumor development in both Pediatrics (MAC), State University of New York, Upstate Medical Uni- cell culture and murine models (4–7). Since its discovery, versity, Syracuse, New York; and Waters Center for Children’s Cancer several studies have identified this particular alteration as a and Blood Disorders, State University of New York, Upstate Cancer relatively uncommon tumor driver in a small subset of GBM Center, Syracuse, New York (MAC). Send correspondence to: Matija Snuderl, MD, Department of Pathology, and low-grade gliomas, including very rare pediatric tumors New York University Langone Health 660 First Avenue, 2nd Floor, New (6, 8, 9). GOPC-ROS1 fusion has also been identified in sev- York, NY 10016; Email: [email protected] eral other cancers, including lung adenocarcinoma (10–12) Methylation profiling at NYU is supported in part by grants from the Fried- and cholangiocarcinoma (13), and ROS1 fusions with other berg Charitable Foundation and the Making Headway Foundation (to M.S.). A portion of this project was supported by the Nationwide Foun- partners have been discovered in many other tumor types dation Pediatric Innovation Fund. (14). Another pathogenic fusion, ZCCHC8-ROS1, was found The authors have no duality or conflicts of interest to declare. to be the underlying oncogenic driver in single a case of VC 2019 American Association of Neuropathologists, Inc. All rights reserved. 1089 Richardson et al J Neuropathol Exp Neurol • Volume 78, Number 12, December 2019 Downloaded from https://academic.oup.com/jnen/article/78/12/1089/5593615 by New York University user on 25 August 2020 FIGURE 1. (A) Coronal and (B) axial T1 þ gadolinium contrast enhancing images of initial tumor presentation in Case 1 demonstrating a heterogeneous mass centered in the left thalamus with focal enhancement and extension into the left lateral ventricle and surrounding structures. Axial T1 þ gadolinium contrast enhancing imaging (C) and axial T2 FLAIR imaging (D) in the same patient demonstrating recurrence. Coronal (E) and axial (F) T1 þ gadolinium contrast enhancing images of Case 2 showing a heterogeneously enhancing intraventricular mass. Axial T1 þ gadolinium contrast enhancing images of case 3 showing a heterogeneously enhancing mass centered in the right temporal lobe (arrowheads) (G) and coronal T2 FLAIR imaging of case 3 showing multinodular tumor in the right temporal lobe (arrowheads) and a noncontiguous nodular component in the right frontal lobe (arrow) (H). congenital GBM (15). Analysis of The Cancer Genome At- MATERIALS AND METHODS las (TCGA) dataset also suggested that GOPC-ROS1 fusion may result in shorter overall survival in adult patients with Clinical Histories GBM (6). While this gene fusion product may be difficult to Case 1 readily detect due to the size of the microdeletion at 6q22 and the inability of break-apart FISH probes to identify this A 4-year-old previously healthy female patient present- particular rearrangement, commercially available immuno- ing with seizure and rapid decline of mental status was found histochemical stains for ROS1 are often positive in cases to have a 3.1 Â 2.8 Â 2.5 cm tumor in the left thalamus with fo- with ROS1 rearrangement with any number of fusion part- cal contrast enhancement extending into the left basal ganglia, ners (6, 11, 12). left temporal lobe, and left ventricle, resulting in hydrocepha- In this study, we identified 3 pediatric patients with lus (Fig. 1A, B). She underwent ventriculoperitoneal shunt clinically similar supratentorial brain tumors, diagnosed as placement and resection of the tumor which showed pilocytic- pilocytic astrocytoma, glioneuronal tumor, and/or GBM af- like morphology with low proliferative activity. The patient ter initial resection. Two of the 3 cases had strikingly similar was treated with carboplatin and vincristine. Over the next histology, including mixed astrocytic and oligodendroglial- 3 years, there was slow, progressive increase in tumor size like features, with diffuse glial fibrillary acidic protein (Fig. 1C, D) requiring tumor debulking and repeat administra- (GFAP) staining and focal islands of synaptophysin- tion of carboplatin and vincristine with additional vinblastine. reactive, NeuN-negative cells. Case 1 appeared to be low- The results of the second surgery showed similar histology but grade on histologic exam of the initial resection specimen; the tumor then had higher-grade features, including increased however, it recurred with features suggestive of anaplasia. proliferative activity and focal necrosis. Two years later, after Case 2 had focal high-grade features on the initial resection additional tumor growth she received left-sided laser ablation specimen. Case 3 had high-grade astrocytic features with of the thalamic tumor and repeat biopsy for additional molecu- diffusely infiltrating components. Methylation profiling lar characterization, followed by 4 cycles of Temodar and failed to classify these tumors to known tumor entities pre- Avastin, complicated by myelosuppression, with radiologic sent in the current version of the methylation classifier with evidence of further tumor progression (Table). a high degree of certainty. Subsequent whole-genome copy number profiling demonstrated microdeletions at 6q22, and Case 2 DNA and RNA sequencing using next generation sequencing (NGS) methods demonstrated GOPC-ROS1 fusion in all A 5-year-old previously healthy male patient presented 3 cases. with 3–4 weeks of somnolence, emesis, and headaches was 1090 J Neuropathol Exp Neurol TABLE. Summary of Radiologic, Histologic, Immunohistochemical, and Molecular Data in Cases 1–3 Age Gender Imaging Findings Histology Immunohistochemistry NGS Results Copy Number Pro- Diagnosis filing Results

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