Infiltrating gliomas with FGFR alterations: Histologic features, genetic alterations, and potential clinical implications

Dono, Antonio; Achi, Hanadi El; Bundrant, Bethany E.; Goli, Puneetha S.; Zhu, Ping; Ozkizilkaya, Hanim I.; Esquenazi, Yoshua; Ballester, Leomar Y.

doi:10.3233/cbm-220041

Cited by 3 publications

(2 citation statements)

References 47 publications

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“…This could stem from the bidirectional effects of TERT mutations, where the neuroprotection and tumor growth effects counteract each other. Furthermore, the fibroblast growth factor receptor (FGFR) gene, frequently altered in cancer, particularly in diffuse gliomas (64.3%) (Dono et al 2023 ), has been found played a potential role in neural architecture in central demyelinating diseases (Zhang et al 2023 ). FGFR proved to help manage neuroinflammation and promote nerve repair and recovery of motor function in multiple sclerosis (MS) patients (Zhang et al 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular Determinants of Neurocognitive Deficits in Glioma: Based on 2021 WHO Classification

Zhang,

Yang,

Xia

et al. 2024

J Mol Neurosci

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Cognitive impairment is a common feature among patients with diffuse glioma. The objective of the study is to investigate the relationship between preoperative cognitive function and clinical as well as molecular factors, firstly based on the new 2021 World Health Organization’s updated classification of central nervous system tumors. A total of 110 diffuse glioma patients enrolled underwent preoperative cognitive assessments using the Mini-Mental State Examination and Montreal Cognitive Assessment. Clinical information was collected from medical records, and gene sequencing was performed to analyze the 18 most influenced genes. The differences in cognitive function between patients with and without glioblastoma were compared under both the 2016 and 2021 WHO classification of tumors of the central nervous system to assess their effect of differentiation on cognition. The study found that age, tumor location, and glioblastoma had significant differences in cognitive function. Several genetic alterations were significantly correlated with cognition. Especially, IDH, CIC, and ATRX are positively correlated with several cognitive domains, while most other genes are negatively correlated. For most focused genes, patients with a low number of genetic alterations tended to have better cognitive function. Our study suggested that, in addition to clinical characteristics such as age, histological type, and tumor location, molecular characteristics play a crucial role in cognitive function. Further research into the mechanisms by which tumors affect brain function is expected to enhance the quality of life for glioma patients. This study highlights the importance of considering both clinical and molecular factors in the management of glioma patients to improve cognitive outcomes.

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Section: Discussionmentioning

confidence: 99%

Molecular Determinants of Neurocognitive Deficits in Glioma: Based on 2021 WHO Classification

Zhang,

Yang,

Xia

et al. 2024

J Mol Neurosci

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“…Some studies have highlighted differences in methylation profiles, tumor mutational burdens (TMBs), and copy number alterations between F3T3-positive and -negative GBMs [5,12]. Some previous studies have been conducted on F3T3-positive GBMs from multiinstitutional cohorts [8,13], but their clinicopathological features remain to be clarified. In this study, we aimed to comprehensively analyze the clinical manifestations, imaging findings, histological features, and molecular characteristics of 25 consecutive cases of F3T3-positive GBM diagnosed at a single institution.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological and Molecular Characteristics of IDH-Wildtype Glioblastoma with FGFR3::TACC3 Fusion

Bae,

Lee,

Hwang

et al. 2024

Biomedicines

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The World Health Organization Classification of Tumors of the Central Nervous System recently incorporated histological features, immunophenotypes, and molecular characteristics to improve the accuracy of glioblastoma (GBM) diagnosis. FGFR3::TACC3 (F3T3) fusion has been identified as an oncogenic driver in IDH-wildtype GBMs. Recent studies have demonstrated the potential of using FGFR inhibitors in clinical trials and TACC3-targeting agents in preclinical models for GBM treatment. However, there is limited information on the clinicopathological and genetic features of IDH-wildtype GBMs with F3T3 fusion. The aim of this study was to comprehensively investigate the clinical manifestations, histological features, and mutational profiles of F3T3-positive GBMs. Between September 2017 and February 2023, 25 consecutive cases (5.0%) of F3T3-positive GBM were extracted from 504 cases of IDH-wildtype GBM. Clinicopathological information and targeted sequencing results obtained from 25 primary and 4 recurrent F3T3-positive GBMs were evaluated and compared with those from F3T3-negative GBMs. The provisional grades determined by histology only were distributed as follows: 4 (26/29; 89.7%), 3 (2/29; 6.9%), and 2 (1/29; 3.4%). Grade 2–3 tumors were ultimately diagnosed as grade 4 GBMs based on the identification of the TERT promoter mutation and the combined gain of chromosome 7 and loss of chromosome 10 (7+/10−). F3T3-positive GBMs predominantly affected women (2.6 females per male). The mean age of patients with an F3T3-positive GBM at initial diagnosis was 62 years. F3T3-positive GBMs occurred more frequently in the cortical locations compared to F3T3-negative GBMs. Imaging studies revealed that more than one-third (12/29; 41.4%) of F3T3-positive GBMs displayed a circumscribed tumor border. Seven of the seventeen patients (41.2%) whose follow-up periods exceeded 20 months died of the disease. Histologically, F3T3-positive GBMs more frequently showed curvilinear capillary proliferation, palisading nuclei, and calcification compared to F3T3-negative GBMs. Molecularly, the most common alterations observed in F3T3-positive GBMs were TERT promoter mutations and 7+/10−, whereas amplifications of EGFR, PDGFRA, and KIT were not detected at all. Other genetic alterations included CDKN2A/B deletion, PTEN mutation, TP53 mutation, CDK4 amplification, and MDM2 amplification. Our observations suggest that F3T3-positive GBM is a distinct molecular subgroup of the IDH-wildtype GBM. Both clinicians and pathologists should consider this rare entity in the differential diagnosis of diffuse astrocytic glioma to make an accurate diagnosis and to ensure appropriate therapeutic management.

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From signalling pathways to targeted therapies: unravelling glioblastoma’s secrets and harnessing two decades of progress

Dewdney,

Jenkins,

Best

et al. 2023

Sig Transduct Target Ther

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Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms of therapeutic resistance, and poor survival rates for both adult and paediatric patients alike. Despite advancements in brain cancer research driven by a technological revolution, translating our understanding of glioblastoma pathogenesis into improved clinical outcomes remains a critical unmet need. This review emphasises the intricate role of receptor tyrosine kinase signalling pathways, epigenetic mechanisms, and metabolic functions in glioblastoma tumourigenesis and therapeutic resistance. We also discuss the extensive efforts over the past two decades that have explored targeted therapies against these pathways. Emerging therapeutic approaches, such as antibody-toxin conjugates or CAR T cell therapies, offer potential by specifically targeting proteins on the glioblastoma cell surface. Combination strategies incorporating protein-targeted therapy and immune-based therapies demonstrate great promise for future clinical research. Moreover, gaining insights into the role of cell-of-origin in glioblastoma treatment response holds the potential to advance precision medicine approaches. Addressing these challenges is crucial to improving outcomes for glioblastoma patients and moving towards more effective precision therapies.

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Infiltrating gliomas with FGFR alterations: Histologic features, genetic alterations, and potential clinical implications

Cited by 3 publications

References 47 publications

Molecular Determinants of Neurocognitive Deficits in Glioma: Based on 2021 WHO Classification

Molecular Determinants of Neurocognitive Deficits in Glioma: Based on 2021 WHO Classification

Clinicopathological and Molecular Characteristics of IDH-Wildtype Glioblastoma with FGFR3::TACC3 Fusion

From signalling pathways to targeted therapies: unravelling glioblastoma’s secrets and harnessing two decades of progress

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