J. M. Figueroa, J. Skog, J. Akers, H. Li, R. Komotar, R. Jensen, F. Ringel, I. Yang, S. Kalkanis, R. Thompson, L. LoGuidice, E. Berghoff, A. Parsa, L. Liau, W. Curry, D. Cahill, C. Bettegowda, F. F. Lang, E. A. Chiocca, J. Henson, R. Kim, X. Breakefield, C. Chen, K. Messer, F. Hochberg, and B. S. Carter. Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients. Neuro Oncol, 19(11):1494–1502, Oct 2017. [PubMed Central:\href https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737576PMC5737576] [DOI:\href https://dx.doi.org/10.1093/neuonc/nox08510.1093/neuonc/nox085] [PubMed:\href https://www.ncbi.nlm.nih.gov/pubmed/2012925120129251].
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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.