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Neuro Oncol. 2017 Oct 19;19(11):1494-1502. doi: 10.1093/neuonc/nox085.

Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients.

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Division of Neurosurgery and Division of Biostatistics, University of California San Diego (UCSD), San Diego, California, USA; Exosome Diagnostics, Inc, New York, New York, USA; Department of Neurosurgery, University of Miami, Miami, Florida, USA; Department of Neurosurgery, University of Utah, Salt Lake City, Utah, USA; Neurochirurgische Klinik und Poliklinik, Munchen, Germany; Henry Ford Health System, Department of Neurosurgery, Detroit, Michigan, USA; Department of Neurosurgery, Vanderbilt University, Nashville, Tennessee, USA; Department of Neurosurgery, Northwestern University, Chicago, Illinois, USA; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California, USA; Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA; Department of Neurosurgery, MD Anderson Cancer Center, Houston, Texas, USA; Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Neurology, Swedish Medical Center, Seattle, Washington, USA; Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.



RNAs within extracellular vesicles (EVs) have potential as diagnostic biomarkers for patients with cancer and are identified in a variety of biofluids. Glioblastomas (GBMs) release EVs containing RNA into cerebrospinal fluid (CSF). Here we describe a multi-institutional study of RNA extracted from CSF-derived EVs of GBM patients to detect the presence of tumor-associated amplifications and mutations in epidermal growth factor receptor (EGFR).


CSF and matching tumor tissue were obtained from patients undergoing resection of GBMs. We determined wild-type (wt)EGFR DNA copy number amplification, as well as wtEGFR and EGFR variant (v)III RNA expression in tumor samples. We also characterized wtEGFR and EGFRvIII RNA expression in CSF-derived EVs.


EGFRvIII-positive tumors had significantly greater wtEGFR DNA amplification (P = 0.02) and RNA expression (P = 0.03), and EGFRvIII-positive CSF-derived EVs had significantly more wtEGFR RNA expression (P = 0.004). EGFRvIII was detected in CSF-derived EVs for 14 of the 23 EGFRvIII tissue-positive GBM patients. Conversely, only one of the 48 EGFRvIII tissue-negative patients had the EGFRvIII mutation detected in their CSF-derived EVs. These results yield a sensitivity of 61% and a specificity of 98% for the utility of CSF-derived EVs to detect an EGFRvIII-positive GBM.


Our results demonstrate CSF-derived EVs contain RNA signatures reflective of the underlying molecular genetic status of GBMs in terms of wtEGFR expression and EGFRvIII status. The high specificity of the CSF-derived EV diagnostic test gives us an accurate determination of positive EGFRvIII tumor status and is essentially a less invasive "liquid biopsy" that might direct mutation-specific therapies for GBMs.


CSF; EGFRvIII; biomarker; glioma; vesicle

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