Targeting gene fusions in glioma

Kim, Peter L

doi:10.1097/wco.0000000000000991

Cited by 7 publications

(4 citation statements)

References 46 publications

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“…Several clinical trials are currently underway, such as NCT02650401, NCT04655404 and NCT02637687, focusing on the treatment of NTRK fusion gliomas. Targeted therapies utilizing NTRK inhibitors have shown promising results in patients with this condition [23].…”

Section: Discussionmentioning

confidence: 99%

Identification of the clinical and genetic characteristics of gliomas with gene fusions by integrated genomic and transcriptomic analysis

Zhang

Que

et al. 2023

Preprint

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The identification of oncogenic gene fusions in diffuse gliomas may serve as potential therapeutic targets and prognostic indicators, representing a novel strategy for treating gliomas consistent with the principles of personalized medicine. This study identified detectable oncogene fusions in glioma patients through an integrated analysis of genomic and transcriptomic data, which encompassed whole exon sequencing and next-generation RNA sequencing. Additionally, this study also conducted a comparison of the genetic characteristics, tumor microenvironment, mutation burden and survival between glioma patients with or without gene fusions. A total of 68 glioma patients were enrolled in this study, including glioblastoma (GBM), low grade glioma (LGG) and diffuse midline glioma (DMG). 14 cases of GBM patients (51.9%, 14/27) were found to harbor the following 70 oncogenic gene fusions: ROS1 (n = 8), NTRK (n = 5), KIF5 (n = 5), RET (n = 3) and other infrequent gene fusions (n = 49). A total of 11 gene fusions were identified in 8 LGG patients (32.0%, 8/25) and seven gene fusions were identified in one DMG patient (16.7%, 1/6). In GBM patient group, five genes including HOXA3, ACTB, CDK5, GNA12 and CARD11 exhibited a statistically significant higher copy number amplification frequency in the GBM group without gene fusions compared to that in the GBM group with gene fusions. In LGG patient group, CDK5 gene was also found to exhibit a statistically significant higher amplification frequency in the LGG group without gene fusions. Additionally, KMT2D exhibited a statistically significant higher mutation frequency in the LGG group with gene fusions compared to that in the LGG group without gene fusions. Comparison of the other genetic characteristics including immune cell infiltration score, tumor mutation burden (TMB), and microsatellite instability (MSI). The results showed no statistically significant differences were observed between fusion and non-fusion group of GBM and LGG. The survival analysis revealed that GBM patients without gene fusions exhibited a longer median survival (737 days) compared to GBM patients with gene fusions (642 days), but without a statistical significancy. Our study has identified a set of gene fusions present in gliomas, including a number of novel gene fusions that have not been previously reported. We have also elucidated the underlying genetic characteristics of glioma with gene fusions. Collectively, our findings have the potential to inform future clinical treatment strategies for patients with glioma.

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Section: Discussionmentioning

confidence: 99%

Identification of the clinical and genetic characteristics of gliomas with gene fusions by integrated genomic and transcriptomic analysis

Zhang

Que

et al. 2023

Preprint

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“…TPR encodes a leucine zipper domain that constitutively dimerizes the Met kinase domain in the absence of ligand [31]. This fusion protein is cytosolic and constitutively activates downstream signalling pathways [74]. Multiple fusions have been detected in GBM.…”

Section: Fusion Genesmentioning

confidence: 99%

Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions

Al-Ghabkari,

Huang,

Park

2024

Cells

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Brain tumors represent a heterogeneous group of neoplasms characterized by a high degree of aggressiveness and a poor prognosis. Despite recent therapeutic advances, the treatment of brain tumors, including glioblastoma (GBM), an aggressive primary brain tumor associated with poor prognosis and resistance to therapy, remains a significant challenge. Receptor tyrosine kinases (RTKs) are critical during development and in adulthood. Dysregulation of RTKs through activating mutations and gene amplification contributes to many human cancers and provides attractive therapeutic targets for treatment. Under physiological conditions, the Met RTK, the hepatocyte growth factor/scatter factor (HGF/SF) receptor, promotes fundamental signaling cascades that modulate epithelial-to-mesenchymal transition (EMT) involved in tissue repair and embryogenesis. In cancer, increased Met activity promotes tumor growth and metastasis by providing signals for proliferation, survival, and migration/invasion. Recent clinical genomic studies have unveiled multiple mechanisms by which MET is genetically altered in GBM, including focal amplification, chromosomal rearrangements generating gene fusions, and a splicing variant mutation (exon 14 skipping, METex14del). Notably, MET overexpression contributes to chemotherapy resistance in GBM by promoting the survival of cancer stem-like cells. This is linked to distinctive Met-induced pathways, such as the upregulation of DNA repair mechanisms, which can protect tumor cells from the cytotoxic effects of chemotherapy. The development of MET-targeted therapies represents a major step forward in the treatment of brain tumours. Preclinical studies have shown that MET-targeted therapies (monoclonal antibodies or small molecule inhibitors) can suppress growth and invasion, enhancing the efficacy of conventional therapies. Early-phase clinical trials have demonstrated promising results with MET-targeted therapies in improving overall survival for patients with recurrent GBM. However, challenges remain, including the need for patient stratification, the optimization of treatment regimens, and the identification of mechanisms of resistance. This review aims to highlight the current understanding of mechanisms underlying MET dysregulation in GBM. In addition, it will focus on the ongoing preclinical and clinical assessment of therapies targeting MET dysregulation in GBM.

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“… 86–88 Gene fusions appear to be particularly attractive targets, though thus far with limited efficacy for CNS tumors. 11 , 89 Panel diagnostics require less tumor material and can at times provide a diagnosis in the absence of a clear histopathological tumor diagnosis, avoiding the need for a repeat biopsy. 90 This is very similar to other areas in oncology where the role of advanced molecular diagnostics is increasing rapidly: optimal oncological treatment starts with the right diagnosis in all cases.…”

Section: Practical Implicationsmentioning

confidence: 99%

Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline

et al. 2023

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In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types. For those tumors, an integrated, ‘histomolecular’ diagnosis is required. A variety of approaches exists for determining the status of the underyling molecular markers. The present guideline focuses on the methods that can be used for assessment of the currently most informative diagnostic and prognostic molecular markers for the diagnosis of gliomas, glioneuronal and neuronal tumors. The main characteristics of the molecular methods are systematically discussed, followed by recommendations and information on available evidence levels for diagnostic measures. The recommendations cover DNA and RNA next-generation-sequencing, methylome profiling, and select assays for single/limited target analysis, including immunohistochemistry. Additionally, because of its importance as a predictive marker in IDH-wildtype glioblastomas, tools for the analysis of MGMT promoter status are covered. A structured overview of the different assays with their characteristics, especially their advantages and limitations, is provided, and requirements for input material and reporting of results are clarified. General aspects of molecular diagnostic testing regarding clinical relevance, accessibility, cost, implementation, regulatory and ethical aspects are discussed as well. Finally, we provide an outlook on new developments in the landscape of molecular testing technologies in neuro-oncology.

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Targeting gene fusions in glioma

Cited by 7 publications

References 46 publications

Identification of the clinical and genetic characteristics of gliomas with gene fusions by integrated genomic and transcriptomic analysis

Identification of the clinical and genetic characteristics of gliomas with gene fusions by integrated genomic and transcriptomic analysis

Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions

Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline

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