Novel TPR::ROS1 Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma

• Published in: Cancer genomics & proteomics Vol. 19; no. 6; pp. 711 - 726
• Main Authors: DELAND, LILY, KEANE, SIMON, BONTELL, THOMAS OLSSON, FAGMAN, HENRIK, SJÖGREN, HELENE, LIND, ANDERS E., CARÉN, HELENA, TISELL, MAGNUS, NILSSON, JONAS A., EJESKÄR, KATARINA, SABEL, MAGNUS, ABEL, FRIDA
• Format: Journal Article
• Language: English
• Published: Athens International Institute of Anticancer Research 01.11.2022
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Basic Medicine; Brain cancer; Brain tumors; Cell and Molecular Biology; Cell- och molekylärbiologi; childhood cancer; chromosomal rearrangement; Clinical Medicine; Extracellular signal-regulated kinase; Functional analysis; Fusion; Fusion protein; Gene Rearrangement; Gene sequencing; Genes; genetics; Genomes; Glioma; HEK293 Cells; Histology; Humans; Immunohistochemistry; Infant; Infants; Kinases; Klinisk medicin; Lung Neoplasms; Lysates; Male; MAP kinase; Medical Genetics and Genomics; Medicinsk genetik och genomik; Medicinska och farmaceutiska grundvetenskaper; metabolism; Oncogene Proteins; pathology; Patients; Pediatric glioma; Pediatrics; Phosphatidylinositol 3-Kinases; Phosphorylation; precision medicine; Protein-tyrosine kinase receptors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Ribonucleic acid; RNA; Solid tumors; Tissue analysis; Tissues; TKI; Transcriptomes; Translational Medicine TRIM; Translationell medicin TRIM; Tumors; Tyrosine; tyrosine kinases; Ventricle; Ventricles (cerebral)
• ISSN: 1109-6535; 1790-6245; 1790-6245
• DOI: 10.21873/cgp.20354

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.