Rare but recurrent ROS1 fusions resulting from chromosome 6q22 microdeletions are targetable oncogenes in glioma Journal Article


Authors: Davare, M. A.; Henderson, J. J.; Agarwal, A.; Wagner, J. P.; Iyer, S. R.; Shah, N.; Woltjer, R.; Somwar, R.; Gilheeney, S. W.; DeCarvalo, A.; Mikkelson, T.; Van Meir, E. G.; Ladanyi, M.; Druker, B. J.
Article Title: Rare but recurrent ROS1 fusions resulting from chromosome 6q22 microdeletions are targetable oncogenes in glioma
Abstract: Purpose: 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. Experimental Design: 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. Results: 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 phar-macologic inhibition with several ROS1 inhibitors even when occurring concurrently with other cancer hotspot aberrations frequently associated with glioblastoma. Oral monotherapy with a brain-permeable ROS1 inhibitor, lorlatinib, significantly prolonged survival in an intracranially xenografted tumor model generated from a ROS1 fusion-positive glioblastoma cell line. Conclusions: Our findings highlight that CNS tumors should be specifically interrogated for these rare intrachromosomal 6q22 microdeletion events that generate actionable ROS1 fusions. ROS1 fusions in primary brain cancer may be amenable for clinical intervention with kinase inhibitors, and this holds the potential of novel treatment paradigms in these treatment-refractory cancer types, particularly in glioblastoma. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 24
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-12-01
Start Page: 6471
End Page: 6482
Language: English
DOI: 10.1158/1078-0432.Ccr-18-1052
PROVIDER: scopus
PMCID: PMC6295214
PUBMED: 30171048
DOI/URL:
Notes: Clin. Cancer Res. -- Export Date: 2 January 2019 -- Article -- CODEN: CCREF C2 - 30171048 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Marc Ladanyi
    851 Ladanyi
  2. Romel Somwar
    33 Somwar