Rare but Recurrent ROS1 Fusions Resulting From Chromosome 6q22 Microdeletions are Targetable Oncogenes in Glioma.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Monika A DavareBrian J Druker

Abstract

Gliomas, a genetically heterogeneous group of primary central nervous system tumors, continue to pose a significant clinical challenge. Discovery of chromosomal rearrangements involving kinase genes has enabled precision therapy, and improved outcomes in several malignancies. Positing that similar benefit could be accomplished for patients with brain cancer, we evaluated The Cancer Genome Atlas (TCGA) glioblastoma dataset. Functional validation of the oncogenic potential and inhibitory sensitivity of discovered ROS1 fusions was performed using three independent cell-based model systems, and an in vivo murine xenograft study. In silico analysis revealed previously unreported intrachromosomal 6q22 microdeletions that generate ROS1-fusions from TCGA glioblastoma dataset. ROS1 fusions in primary glioma and ependymoma were independently corroborated from MSK-IMPACT and Foundation Medicine clinical datasets. GOPC-ROS1 is a recurrent ROS1 fusion in primary central nervous system (CNS) tumors. CEP85L-ROS1 and GOPC-ROS1 are transforming oncogenes in cells of astrocytic lineage, and amenable to pharmacologic inhibition with several ROS1 inhibitors even when occurring concurrently with other cancer hotspot aberrations frequently associate...Continue Reading

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Citations

Mar 23, 2019·Oncotarget·Igor OdintsovMonika A Davare
Oct 19, 2019·Journal of Neuropathology and Experimental Neurology·Timothy E RichardsonMatija Snuderl
Mar 14, 2020·Acta Neuropathologica Communications·Scott RyallCynthia Hawkins
Aug 8, 2020·Nature Reviews. Clinical Oncology·Alexander DrilonMonika A Davare
May 22, 2019·Journal of Cellular Biochemistry·Peng XieXiaohua Zuo
Dec 19, 2020·International Journal of Cancer. Journal International Du Cancer·Richard S P HuangJeffrey S Ross
Mar 7, 2021·Cancers·Yusuke FunakoshiMasahiro Mizoguchi
Mar 19, 2021·Virchows Archiv : an International Journal of Pathology·Keisuke GotoArnaud de la Fouchardière
Oct 22, 2021·Frontiers in Neurology·Gan YouClark C Chen

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