检测脑胶质母细胞瘤患者脑脊液来源的细胞外囊泡中的野生型 EGFR 扩增和 EGFRvIII 突变。
Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients.
机构信息
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.
出版信息
Neuro Oncol. 2017 Oct 19;19(11):1494-1502. doi: 10.1093/neuonc/nox085.
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.
背景
细胞外囊泡（EVs）中的 RNA 具有作为癌症患者诊断生物标志物的潜力，并在各种生物体液中被鉴定出来。胶质母细胞瘤（GBM）会将含有 RNA 的 EV 释放到脑脊液（CSF）中。在这里，我们描述了一项多机构研究，该研究对从 GBM 患者 CSF 衍生的 EV 中提取的 RNA 进行了分析，以检测表皮生长因子受体（EGFR）中存在的肿瘤相关扩增和突变。
方法
从接受 GBM 切除术的患者中获取 CSF 和匹配的肿瘤组织。我们确定了肿瘤样本中野生型（wt）EGFR DNA 拷贝数扩增，以及 wtEGFR 和 EGFR 变体（v）III RNA 表达。我们还对 CSF 衍生的 EV 中 wtEGFR 和 EGFRvIII RNA 表达进行了特征描述。
结果
EGFRvIII 阳性肿瘤的 wtEGFR DNA 扩增（P = 0.02）和 RNA 表达（P = 0.03）显著更高，并且 EGFRvIII 阳性 CSF 衍生的 EV 中 wtEGFR RNA 表达显著更多（P = 0.004）。在 23 例 EGFRvIII 组织阳性 GBM 患者中，有 14 例在 CSF 衍生的 EV 中检测到 EGFRvIII。相反，在 48 例 EGFRvIII 组织阴性患者中，只有 1 例在其 CSF 衍生的 EV 中检测到 EGFRvIII 突变。这些结果得出 CSF 衍生 EV 用于检测 EGFRvIII 阳性 GBM 的灵敏度为 61%，特异性为 98%。
结论
我们的结果表明，CSF 衍生的 EV 包含反映 GBM 潜在分子遗传状态的 RNA 特征，涉及 wtEGFR 表达和 EGFRvIII 状态。CSF 衍生 EV 诊断测试的高特异性使我们能够准确确定阳性 EGFRvIII 肿瘤状态，并且本质上是一种侵袭性较小的“液体活检”，可以为 GBM 指导突变特异性治疗。
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