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GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors.

Abstract

ROS1 is a transmembrane receptor tyrosine kinase proto-oncogene that has been shown to have rearrangements with several genes in glioblastoma and other neoplasms, including intrachromosomal fusion with GOPC due to microdeletions at 6q22.1. ROS1 fusion events are important findings in these tumors, as they are potentially targetable alterations with newer tyrosine kinase inhibitors; however, whether these tumors represent a distinct entity remains unknown. In this report, we identify 3 cases 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 detection of oncogenic mutation and fusion events to fully characterize the genetic and epigenetic alterations present in these tumors. Two of 3 tumors showed pilocytic features with focal expression of synaptophysin staining and variable high-grade histologic features; the third tumor aligned best with glioblastoma and showed no evidence of neuronal differentiation. Copy number profiling revealed chromosome 6q22 microdeletions corresponding to the GOPC-ROS1 fusion in all 3 cases and methylation profiling showed that the tumors did not cluster together as a single entity or within known methylation classes by t-Distributed Stochastic Neighbor Embedding.

Authors+Show Affiliations

Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).No affiliation info availableDepartment of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York (TER, KM); Department of Pediatrics (KT); Department of Pathology (VV, JS, CMW, GJ, MS), New York University Langone Health, New York, New York; Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University (CRP, CEC, DRB); Department of Neurological Surgery, Nationwide Children's Hospital (JRL); Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University (MSA); Nationwide Children's Hospital, The Institute for Genomic Medicine (KMS, CEC), Columbus, Ohio; Department of Neurosurgery (ZT-S); Department of Pediatrics (MAC), State University of New York, Upstate Medical University, Syracuse, New York; Waters Center for Children's Cancer and Blood Disorders, State University of New York, Upstate Cancer Center, Syracuse, New York (MAC).No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31626289

Citation

Richardson, Timothy E., et al. "GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors." Journal of Neuropathology and Experimental Neurology, 2019.
Richardson TE, Tang K, Vasudevaraja V, et al. GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors. J Neuropathol Exp Neurol. 2019.
Richardson, T. E., Tang, K., Vasudevaraja, V., Serrano, J., William, C. M., Mirchia, K., ... Snuderl, M. (2019). GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors. Journal of Neuropathology and Experimental Neurology, doi:10.1093/jnen/nlz093.
Richardson TE, et al. GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors. J Neuropathol Exp Neurol. 2019 Sep 16; PubMed PMID: 31626289.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors. AU - Richardson,Timothy E, AU - Tang,Karen, AU - Vasudevaraja,Varshini, AU - Serrano,Jonathan, AU - William,Christopher M, AU - Mirchia,Kanish, AU - Pierson,Christopher R, AU - Leonard,Jeffrey R, AU - AbdelBaki,Mohamed S, AU - Schieffer,Kathleen M, AU - Cottrell,Catherine E, AU - Tovar-Spinoza,Zulma, AU - Comito,Melanie A, AU - Boué,Daniel R, AU - Jour,George, AU - Snuderl,Matija, Y1 - 2019/09/16/ PY - 2019/07/05/received PY - 2019/08/02/revised PY - 2019/09/05/accepted PY - 2019/10/19/entrez KW - 6q22 KW - Astrocytoma KW - Brain tumor KW - GOPC KW - Pediatric glioma KW - ROS1 JF - Journal of neuropathology and experimental neurology JO - J. Neuropathol. Exp. Neurol. N2 - ROS1 is a transmembrane receptor tyrosine kinase proto-oncogene that has been shown to have rearrangements with several genes in glioblastoma and other neoplasms, including intrachromosomal fusion with GOPC due to microdeletions at 6q22.1. ROS1 fusion events are important findings in these tumors, as they are potentially targetable alterations with newer tyrosine kinase inhibitors; however, whether these tumors represent a distinct entity remains unknown. In this report, we identify 3 cases 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 detection of oncogenic mutation and fusion events to fully characterize the genetic and epigenetic alterations present in these tumors. Two of 3 tumors showed pilocytic features with focal expression of synaptophysin staining and variable high-grade histologic features; the third tumor aligned best with glioblastoma and showed no evidence of neuronal differentiation. Copy number profiling revealed chromosome 6q22 microdeletions corresponding to the GOPC-ROS1 fusion in all 3 cases and methylation profiling showed that the tumors did not cluster together as a single entity or within known methylation classes by t-Distributed Stochastic Neighbor Embedding. SN - 1554-6578 UR - https://www.unboundmedicine.com/medline/citation/31626289/GOPC-ROS1_Fusion_Due_to_Microdeletion_at_6q22_Is_an_Oncogenic_Driver_in_a_Subset_of_Pediatric_Gliomas_and_Glioneuronal_Tumors L2 - https://academic.oup.com/jnen/article-lookup/doi/10.1093/jnen/nlz093 DB - PRIME DP - Unbound Medicine ER -