The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma

High-grade glioma is one of the most lethal human cancers characterized by extensive tumor heterogeneity. In order to identify cellular and molecular mechanisms that drive tumor heterogeneity of this lethal disease, we performed single-cell RNA sequencing analysis of one high-grade glioma. Accordingly, we analyzed the individual cellular components in the ecosystem of this tumor. We found that tumor-associated macrophages are predominant in the immune microenvironment. Furthermore, we identified five distinct subpopulations of tumor cells, including one cycling, two OPC/NPC-like and two MES-like cell subpopulations. Moreover, we revealed the evolutionary transition from the cycling to OPC/NPC-like and MES-like cells by trajectory analysis. Importantly, we found that SPP1/CD44 interaction plays a critical role in macrophage-mediated activation of MES-like cells by exploring the cell-cell communication among all cellular components in the tumor ecosystem. Finally, we showed that high expression levels of both SPP1 and CD44 correlate with an increased infiltration of macrophages and poor prognosis of glioma patients. Taken together, this study provided a single-cell atlas of one high-grade glioma and revealed a critical role of macrophage-mediated SPP1/CD44 signaling in glioma progression, indicating that the SPP1/CD44 axis is a potential target for glioma treatment.

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Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

10.21203/rs.3.rs-257705/v2 ◽

2021 ◽

Author(s):

Inga-Maria Launonen ◽

Nuppu Lyytikäinen ◽

Julia Casado ◽

Ella Anttila ◽

Angéla Szabó ◽

...

Keyword(s):

Tumor Microenvironment ◽

Single Cell ◽

Single Cells ◽

High Grade ◽

Prognostic Role ◽

Immune Microenvironment ◽

Proteomic Data ◽

Tumor Immune Microenvironment ◽

Cellular Phenotypes

Abstract The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generated spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes (HRwt). We identified a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we found an opposing prognostic role of a proliferative tumor-cell phenotypic subpopulation in the HR-genotypes, which associated with enhanced spatial tumor-immune interactions by the CD8+ and CD4+T-cells in BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the premise to improve immunotherapeutic strategies and patient stratification in HGSC.

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HGG-41. STRUCTURAL VARIANT DRIVERS IN PEDIATRIC HIGH-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.322 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii351-iii351

Author(s):

Frank Dubois ◽

Ofer Shapira ◽

Noah Greenwald ◽

Travis Zack ◽

Jessica W Tsai ◽

...

Keyword(s):

Copy Number ◽

High Grade Glioma ◽

High Grade ◽

Structural Variants ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Effector Domains ◽

Topologically Associating Domains ◽

Genome Wide ◽

Pediatric High Grade Glioma

Abstract BACKGROUND Driver single nucleotide variants (SNV) and somatic copy number aberrations (SCNA) of pediatric high-grade glioma (pHGGs), including Diffuse Midline Gliomas (DMGs) are characterized. However, structural variants (SVs) in pHGGs and the mechanisms through which they contribute to glioma formation have not been systematically analyzed genome-wide. METHODS Using SvABA for SVs as well as the latest pipelines for SCNAs and SNVs we analyzed whole-genome sequencing from 174 patients. This includes 60 previously unpublished samples, 43 of which are DMGs. Signature analysis allowed us to define pHGG groups with shared SV characteristics. Significantly recurring SV breakpoints and juxtapositions were identified with algorithms we recently developed and the findings were correlated with RNAseq and H3K27ac ChIPseq. RESULTS The SV characteristics in pHGG showed three groups defined by either complex, intermediate or simple signature activities. These associated with distinct combinations of known driver oncogenes. Our statistical analysis revealed recurring SVs in the topologically associating domains of MYCN, MYC, EGFR, PDGFRA & MET. These correlated with increased mRNA expression and amplification of H3K27ac peaks. Complex recurring amplifications showed characteristics of extrachromosomal amplicons and were enriched in coding SVs splitting protein regulatory from effector domains. Integrative analysis of all SCNAs, SNVs & SVs revealed patterns of characteristic combinations between potential drivers and signatures. This included two distinct groups of H3K27M DMGs with either complex or simple signatures and different combinations of associated variants. CONCLUSION Recurrent SVs associate with signatures shaped by an underlying process, which can lead to distinct mechanisms to activate the same oncogene.

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Reoperation for Recurrent High-Grade Glioma

Neurosurgery ◽

10.1227/neu.0000000000000486 ◽

2014 ◽

Vol 75 (5) ◽

pp. 491-499 ◽

Cited By ~ 62

Author(s):

Shawn L. Hervey-Jumper ◽

Mitchel S. Berger

Keyword(s):

Patient Selection ◽

Survival Benefit ◽

Performance Status ◽

High Grade Glioma ◽

World Health ◽

Time Interval ◽

Extensive Literature ◽

High Grade ◽

Glioma Recurrence

Abstract Optimal treatment for recurrent high-grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients. In this analysis, we reviewed the literature to examine the role of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence.

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