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

Javier M. Figueroa, Johan Skog, Johnny Akers, Hongying Li, Ricardo Komotar, Randy Jensen, Florian Ringel, Isaac Yang, Steven Kalkanis, Reid Thompson, Lori Loguidice, Emily Berghoff, Andrew Parsa, Linda Liau, William Curry, Daniel Cahill, Chetan Bettegowda, Frederick F. Lang, E. Antonio Chiocca, John HensonRyan Kim, Xandra Breakefield, Clark Chen, Karen Messer, Fred Hochberg, Bob S. Carter

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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 EGFRvIIIpositive 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.

Original languageEnglish (US)
Pages (from-to)1494-1502
Number of pages9
JournalNeuro-Oncology
Volume19
Issue number11
DOIs
StatePublished - Nov 1 2017

Bibliographical note

Funding Information:
This work was supported by TNIH; UH2—ExRNA Biomarkers in Glioma (grant# 5UH2TR000931), NIH; UH2 Supplement— ExRNA Biomarkers in Glioma (grant# UH2TR000931-S1), NIH; UH3—ExRNA Biomarkers in Glioma (grant# 4UH3TR000931-03), NIH; P01—Experimental Therapeutics and Biomonitoring of Glioma—Biorepository Core (grant# 2P01 CA069246-16), ABC2 Foundation; Consortium Study of EGFRvIII in Glioma Exosomes, ABC2 Foundation; miRNA Analysis of CSF Glioma Exosomes.

Funding Information:
The authors acknowledge the Accelerate Brain Cancer Cure (ABC2) foundation and the National Institutes of Health (grant #5UH2/UH3TR000931) for their financial support.

Keywords

  • Biomarker
  • CSF
  • EGFRvIII
  • Glioma
  • Vesicle

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