<i>FGFR1</i>
            actionable mutations, molecular specificities, and outcome of adult midline gliomas

Pïcca, Alberto; Berzero, Giulia; Bielle, Franck; Touat, Mehdi; Savatovsky, Julien; Polivka, Marc; Trisolini, Elena; Meunier, S.; Schmitt, Yohann; Idbaïh, Ahmed; Hoang-Xuân, Khê; Delattre, Jean‐Yves; Mokhtari, Karima; Stefano, Anna Luisa Di; Sanson, Marc

doi:10.1212/wnl.0000000000005658

Cited by 53 publications

(43 citation statements)

References 48 publications

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“…In this cohort, nearly all grade IV IMAs were H3K27M mutants (92%), in line with previous reports, which described a range between 38 and 100% of H3K27M-mutant tumors among HG spinal astrocytomas [1,8,17,25,27,32,35,41,42,44,53]. All of the H3F3A mutations identified in our cohort consisted of the recurrent hotspot p.K27M mutation.…”

Section: Discussionsupporting

confidence: 91%

“…IDH mutations were found in half of the brain astrocytoma cases, but only in 2 of the 61 IMAs (with non-canonical mutations). IDH mutations are generally rare and mostly non-canonical in midline locations [ 35 ]. Previous reports of non-canonical IDH mutations in the spine are scarce and restricted to very few cases [ 8 , 9 , 12 , 41 , 54 ] with Takai et al reporting one case with the same IDH1 p.R132S mutation that we found [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

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Clinical, radiological and molecular characterization of intramedullary astrocytomas

Lebrun¹,

Meléndez²,

Blanchard³

et al. 2020

acta neuropathol commun

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Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX. As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Noncanonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Clinical, radiological and molecular characterization of intramedullary astrocytomas

Lebrun¹,

Meléndez²,

Blanchard³

et al. 2020

acta neuropathol commun

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“…Finally, a total of nine studies were included for meta-analyses comprising of 2819 glioma patients ( Fig. 1) [16,[25][26][27][28][29][30][31][32]. The baseline characteristics of these studies were presented in Table 1.…”

Section: Resultsmentioning

confidence: 99%

The interaction between TERT promoter mutation and MGMT promoter methylation on overall survival of glioma patients: a meta-analysis

et al. 2020

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Background There are controversial results concerning the prognostic implication of TERT promoter mutation in glioma patients concerning MGMT status. In this meta-analysis, we investigated whether there are any interactions of these two genetic markers on the overall survival (OS) of glioma patients. Methods Electronic databases including PubMed and Web of Science were searched for relevant studies. Hazard ratio (HR) and its 95% confidence interval (CI) for OS adjusted for selected covariates were calculated from the individual patient data (IPD), Kaplan-Meier curve (KMC), or directly obtained from the included studies. Results A total of nine studies comprising 2819 glioma patients were included for meta-analysis. Our results showed that TERT promoter mutation was associated with a superior outcome in MGMT-methylated gliomas (HR = 0.73; 95% CI = 0.55–0.98; p-value = 0.04), whereas this mutation was associated with poorer survival in gliomas without MGMT methylation (HR = 1.86; 95% CI = 1.54–2.26; p-value < 0.001). TERT-mutated glioblastoma (GBM) patients with MGMT methylation benefited from temozolomide (TMZ) treatment (HR = 0.33; 95% CI = 0.23–0.47; p-value < 0.001). MGMT methylation was not related with any improvement in OS in TERT-wild type GBMs (HR = 0.80; 95% CI = 0.56–1.15; p-value = 0.23). Conclusions The prognostic value of TERT promoter mutation may be modulated by MGMT methylation status. Not all MGMT-methylated GBM patients may benefit from TMZ; it is possible that only TERT-mutated GBM with MGMT methylation, in particular, may respond.

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“…Glioma has shown amplified levels of many FGFR molecules among which patients displaying poor responses showed increased FGFR1 that was not seen in chemotherapy‐responsive patients . The various downstream signalling targets of this molecule such as PI3K/AKT have already been mentioned above.…”

Section: Discussionmentioning

confidence: 97%

MiR‐3116 sensitizes glioma cells to temozolomide by targeting FGFR1 and regulating the FGFR1/PI3K/AKT pathway

Kong

Cao

et al. 2020

J Cellular Molecular Medi

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| 4677 wileyonlinelibrary.com/journal/jcmm | INTRODUC TI ONGlioma accounts for 30% of brain tumours and 80% malignancies making it a ubiquitous malignancy of the brain. 1,2 While there have been developments to address this condition, the median survival is 12-14 months for the high-grade disease causing the prognosis. 3 One approach is the use of chemotherapy (temozolomide: TMZ) plus surgery and radiotherapy. This approach, however, is challenged by TMZ resistance (inherent and acquired). 4,5 This calls for the addressing of this condition to boost the responses of the malignancy to TMZ. MicroRNAs (MiRNAs) are the small endogenous non-coding RNAs that could inhibit translation or degrade mRNA by base-pairing to the 3′-untranslated region (UTR) of targets to result in the inactivation of the latter. 6,7 Research has shown that miRNAs are oncogenes or tumour suppressors by targeting the cell cycle, cell division, apoptosis and angiogenesis in numerous human cancers. 8 There is also proof of the functioning of miRNAs in the resistance to chemotherapeutic AbstractGlioma is a brain tumour that is often diagnosed, and temozolomide (TMZ) is a common chemotherapeutic drug used in glioma. Yet, resistance to TMZ is a chief hurdle towards curing the malignancy. The current work explores the pathways and involvement of miR-3116 in the TMZ resistance. miR-3116 and FGFR1 mRNA were quantified by real-time PCR in malignant samples and cell lines. Appropriate assays were designed for apoptosis, viability, the ability to form colonies and reporter assays to study the effects of the miR-3116 or FGFR1. The involvement of PI3K/AKT signalling was assessed using Western blotting. Tumorigenesis was evaluated in an appropriate xenograft mouse model in vivo. This work revealed that the levels of miR-3116 dipped in samples resistant to TMZ, while increased miR-3116 caused an inhibition of the tumour features mentioned above to hence augment TMZ sensitivity. miR-3116 was found to target FGFR1. When FGFR1 was overexpressed, resistance to TMZ was augmented and reversed the sensitivity caused by miR-3116. Our findings further confirmed PI3K/AKT signalling pathway is involved in this action. In conclusion, miR-3116 sensitizes glioma cells to TMZ through FGFR1 downregulation and the PI3K/ AKT pathway inactivation. Our results provide a strategy to overcome TMZ resistance in glioma treatment. K E Y W O R D Sdrug resistance, FGFR1, FGFR1/PI3K/AKT, miR-3116, temozolomide

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FGFR1 actionable mutations, molecular specificities, and outcome of adult midline gliomas

Cited by 53 publications

References 48 publications

Clinical, radiological and molecular characterization of intramedullary astrocytomas

Clinical, radiological and molecular characterization of intramedullary astrocytomas

The interaction between TERT promoter mutation and MGMT promoter methylation on overall survival of glioma patients: a meta-analysis

MiR‐3116 sensitizes glioma cells to temozolomide by targeting FGFR1 and regulating the FGFR1/PI3K/AKT pathway

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