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Novel TPR::ROS1 Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma
Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translationell medicin TRIM, Translational Medicine)ORCID iD: 0000-0002-0471-6896
Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden ; Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
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2022 (English)In: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 19, no 6, p. 711-726Article in journal (Refereed) Published
Abstract [en]

BACKGROUND/AIM: Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusion-positive solid tumors. PATIENT AND METHODS: Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed. RESULTS: Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K- and JAK/STAT- pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient. CONCLUSION: We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse. 

Place, publisher, year, edition, pages
Cancer Genomics & Proteomics , 2022. Vol. 19, no 6, p. 711-726
Keywords [en]
childhood cancer, chromosomal rearrangement, Pediatric glioma, precision medicine, TKI, tyrosine kinases
National Category
Cancer and Oncology Medical Genetics
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-22033DOI: 10.21873/cgp.20354PubMedID: 36316040Scopus ID: 2-s2.0-85140937065OAI: oai:DiVA.org:his-22033DiVA, id: diva2:1709852
Funder
Swedish Cancer Society, 2018/825Swedish Cancer Society, 2018/652Swedish Childhood Cancer Foundation, PR2017-0029Swedish Childhood Cancer Foundation, PR2019-0079Swedish Childhood Cancer Foundation, KP2019-0010
Note

CC BY-NC-ND 4.0

Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Correspondence to: Frida Abel

This work was supported by the Swedish Cancer Society (www.cancerfonden.se, grant number 2018/825 to FA and grant number 2018/652 to JAN), the Swedish Children’s Cancer Foundation (www.barncancerfonden.se, grant number PR2017-0029 to FA, PR2019-0079 to KE, and KP2019-0010 to HC), and the ALF-agreement (www.researchweb.org/is/alfgbg, ALFGBG-716231 to FA, ALFGBG-965828 to HC, and ALFGBG-719301 to JAN).

Available from: 2022-11-10 Created: 2022-11-10 Last updated: 2023-01-16Bibliographically approved

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Keane, SimonEjeskär, Katarina

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