Identification of the immune gene expression signature associated with recurrence of high-grade gliomas.
Adria-Jaume RouraBartlomiej GielniewskiPaulina PilancPaulina SzadkowskaMarta MaleszewskaSylwia Katarzyna KrólRyszard CzepkoWojciech KasperaBartosz WojtaśBozena KaminskaPublished in: Journal of molecular medicine (Berlin, Germany) (2020)
High-grade gliomas (HGGs), the most common and aggressive primary brain tumors in adults, inevitably recur due to incomplete surgery or resistance to therapy. Intratumoral genomic and cellular heterogeneity of HGGs contributes to therapeutic resistance, recurrence, and poor clinical outcomes. Transcriptomic profiles of HGGs at recurrence have not been investigated in detail. Using targeted sequencing of cancer-related genes and transcriptomics, we identified single nucleotide variations, small insertions and deletions, copy number aberrations (CNAs), as well as gene expression changes and pathway deregulation in 16 pairs of primary and recurrent HGGs. Most of the somatic mutations identified in primary HGGs were not detected after relapse, suggesting a subclone substitution during the tumor progression. We found a novel frameshift insertion in the ZNF384 gene which may contribute to extracellular matrix remodeling. An inverse correlation of focal CNAs in EGFR and PTEN genes was detected. Transcriptomic analysis revealed downregulation of genes involved in messenger RNA splicing, cell cycle, and DNA repair, while genes related to interferon signaling and phosphatidylinositol (PI) metabolism are upregulated in secondary HGGs when compared to primary HGGs. In silico analysis of the tumor microenvironment identified M2 macrophages and immature dendritic cells as enriched in recurrent HGGs, suggesting a prominent immunosuppressive signature. Accumulation of those cells in recurrent HGGs was validated by immunostaining. Our findings point to a substantial transcriptomic deregulation and a pronounced infiltration of immature dendritic cells in recurrent HGG, which may impact the effectiveness of frontline immunotherapies in the GBM management. KEY MESSAGES: Most of the somatic mutations identified in primary HGGs were not detected after relapse. Focal CNAs in EGFR and PTEN genes are inversely correlated in primary and recurrent HGGs. Transcriptomic changes and distinct immune-related signatures characterize HGG recurrence. Recurrent HGGs are characterized by a prominent infiltration of immature dendritic and M2 macrophages.
Keyphrases
- copy number
- high grade
- dendritic cells
- genome wide
- single cell
- gene expression
- cell cycle
- mitochondrial dna
- dna methylation
- dna repair
- cell proliferation
- free survival
- extracellular matrix
- small cell lung cancer
- immune response
- rna seq
- low grade
- randomized controlled trial
- minimally invasive
- squamous cell carcinoma
- stem cells
- tyrosine kinase
- poor prognosis
- signaling pathway
- molecular docking
- molecular dynamics simulations
- bone marrow
- atomic force microscopy
- long non coding rna
- coronary artery disease
- lymph node metastasis
- genome wide analysis
- drug induced