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Abstract
Sequencing studies have provided novel insights into the heterogeneous molecular landscape of glioblastoma (GBM), unveiling a subset of patients with gene fusions. Tissue biopsy is highly invasive, limited by sampling frequency and incompletely representative of intra-tumor heterogeneity. Extracellular vesicle-based liquid biopsy provides a minimally invasive alternative to diagnose and monitor tumor-specific molecular aberrations in patient biofluids. Here, we used targeted RNA sequencing to screen GBM tissue and the matched plasma of patients (n = 9) for RNA fusion transcripts. We identified two novel fusion transcripts in GBM tissue and five novel fusions in the matched plasma of GBM patients. The fusion transcripts FGFR3-TACC3 and VTI1A-TCF7L2 were detected in both tissue and matched plasma. A longitudinal follow-up of a GBM patient with a FGFR3-TACC3 positive glioma revealed the potential of monitoring RNA fusions in plasma. In summary, we report a sensitive RNA-seq-based liquid biopsy strategy to detect RNA level fusion status in the plasma of GBM patients.
Highlights
Glioblastoma Multiforme (GBM) is the most common malignant primary central nervous system tumor
We explore the possibility of using RNA-seq-based fusion discovery to identify known and novel fusion transcripts in tumor tissue and the matched plasma of patients with GBM
The gene fusions analyzed by the Massachusetts General Hospital (MGH) Solid Fusion Assay and RNA-seq are listed in Table S1 and Table S2, respectively
Summary
Glioblastoma Multiforme (GBM) is the most common malignant primary central nervous system tumor. It is highly aggressive, with a median overall survival of 15–23 months despite aggressive treatment [1]. A recent large scale genomic and transcriptomic sequencing analysis has shed light on the heterogeneous molecular landscape of GBM, with approximately 30–50% of patients harboring gene fusions [2]. Gene fusions are chromosomal alterations formed as a result of translocation, interstitial deletions, or insertions, resulting in a hybrid of two coding or regulatory sequences between genes [3]. Fusion transcripts are hybrid RNA produced as a result of chromosomal rearrangement (DNA level) or trans-splicing and cis splicing between adjacent genes (RNA level), and have been associated with cancer. These, in turn, generate chimeric proteins with altered functions to drive oncogenic pathways [4]
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