Javier M Figueroa1, Johan Skog1, Johnny Akers1, Hongying Li1, Ricardo Komotar1, Randy Jensen1, Florian Ringel1, Isaac Yang1, Steven Kalkanis1, Reid Thompson1, Lori LoGuidice1, Emily Berghoff1, Andrew Parsa1, Linda Liau1, William Curry1, Daniel Cahill1, Chetan Bettegowda1, Frederick F Lang1, E Antonio Chiocca1, John Henson1, Ryan Kim1, Xandra Breakefield1, Clark Chen1, Karen Messer1, Fred Hochberg1, Bob S Carter1. 1. 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.
Abstract
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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