Distribution and favorable prognostic implication of genomic <scp><i>EGFR</i></scp> alterations in <scp><i>IDH</i></scp>‐wildtype glioblastoma

Higa, Nayuta; Akahane, Toshiaki; Hamada, Taiji; Yonezawa, Hajime; Uchida, Hiroyuki; Makino, Ryutaro; Watanabe, Shôji; Takajo, Tomoko; Yokoyama, Seiya; Kirishima, Mari; Matsuo, Keitaro; Shimizu, Fujio; Hanaya, Ryosuke; Tanimoto, Akihide; Yoshimoto, Koji

doi:10.1002/cam4.4939

Cited by 9 publications

(2 citation statements)

References 49 publications

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“…Even though CDKN2A/B deletion predicts worse survival ( Hsu et al, 2022 ), CNA data among PCA-included patients are inconclusive. However, EGFR amplification and mutation are less frequent in green and blue groups, possibly contributing to their inferior outcomes ( Higa et al, 2023 ) even though some literature data on its prognostic value are debatable ( Hobbs et al, 2012 ; Li et al, 2018a ; Alnahhas et al, 2021 ) or indicate the lack of influence on survival ( Ma et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

Kałuzińska-Kołat,

Kołat,

Kośla

et al. 2023

Front. Neurosci.

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IntroductionGlioblastoma (GBM) is notorious for its clinical and molecular heterogeneity, contributing to therapeutic failure and a grim prognosis. WWOX is one of the tumor suppressor genes important in nervous tissue or related pathologies, which was scarcely investigated in GBM for reliable associations with prognosis or disease progression despite known alterations. Recently, we observed a phenotypic heterogeneity between GBM cell lines (U87MG, T98G, U251MG, DBTRG-05MG), among which the anti-GBM activity of WWOX was generally corresponding, but colony growth and formation were inconsistent in DBTRG-05MG. This prompted us to investigate the molecular landscapes of these cell lines, intending to translate them into the clinical context.MethodsU87MG/T98G/U251MG/DBTRG-05MG were subjected to high-throughput sequencing, and obtained data were explored via weighted gene co-expression network analysis, differential expression analysis, functional annotation, and network building. Following the identification of the most relevant DBTRG-distinguishing driver genes, data from GBM patients were employed for, e.g., differential expression analysis, survival analysis, and principal component analysis.ResultsAlthough most driver genes were unique for each cell line, some were inversely regulated in DBTRG-05MG. Alongside driver genes, the differentially-expressed genes were used to build a WWOX-related network depicting protein–protein interactions in U87MG/T98G/U251MG/DBTRG-05MG. This network revealed processes distinctly regulated in DBTRG-05MG, e.g., microglia proliferation or neurofibrillary tangle assembly. POLE4 and HSF2BP were selected as DBTRG-discriminating driver genes based on the gene significance, module membership, and fold-change. Alongside WWOX, POLE4 and HSF2BP expression was used to stratify patients into cell lines-resembling groups that differed in, e.g., prognosis and treatment response. Some differences from a WWOX-related network were certified in patients, revealing genes that clarify clinical outcomes. Presumably, WWOX overexpression in DBTRG-05MG resulted in expression profile change resembling that of patients with inferior prognosis and drug response. Among these patients, WWOX may be inaccessible for its partners and does not manifest its anti-cancer activity, which was proposed in the literature but not regarding glioblastoma or concerning POLE4 and HSF2BP.ConclusionCell lines data enabled the identification of patients among which, despite high expression of WWOX tumor suppressor, no advantageous outcomes were noted due to the cancer-promoting profile ensured by other genes.

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Section: Resultsmentioning

confidence: 99%

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

Kałuzińska-Kołat,

Kołat,

Kośla

et al. 2023

Front. Neurosci.

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“…The previously classified GBs with IDH mutations have been reclassified as astrocytomas with IDH mutations in grade 4 [ 41 ]. The molecular characteristics of this novel tumor type make EGFR a potential diagnostic and prognostic biomarker [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Prognostic Factors in Adult Diffuse Gliomas: A 10-Year Experience at a Single Institution

Barzegar Behrooz,

Darzi Ramandi,

Latifi-Navid

et al. 2024

Cancers

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Gliomas are primary brain lesions involving cerebral structures without well-defined boundaries and constitute the most prevalent central nervous system (CNS) neoplasms. Among gliomas, glioblastoma (GB) is a glioma of the highest grade and is associated with a grim prognosis. We examined how clinical variables and molecular profiles may have affected overall survival (OS) over the past ten years. A retrospective study was conducted at Sina Hospital in Tehran, Iran and examined patients with confirmed glioma diagnoses between 2012 and 2020. We evaluated the correlation between OS in GB patients and sociodemographic as well as clinical factors and molecular profiling based on IDH1, O-6-Methylguanine-DNA Methyltransferase (MGMT), TERTp, and epidermal growth factor receptor (EGFR) amplification (EGFR-amp) status. Kaplan–Meier and multivariate Cox regression models were used to assess patient survival. A total of 178 patients were enrolled in the study. The median OS was 20 months, with a 2-year survival rate of 61.0%. Among the 127 patients with available IDH measurements, 100 (78.7%) exhibited mutated IDH1 (IDH1-mut) tumors. Of the 127 patients with assessed MGMT promoter methylation (MGMTp-met), 89 (70.1%) had MGMT methylated tumors. Mutant TERTp (TERTp-mut) was detected in 20 out of 127 cases (15.7%), while wildtype TERTp (wildtype TERTp-wt) was observed in 107 cases (84.3%). Analyses using multivariable models revealed that age at histological grade (p < 0.0001), adjuvant radiotherapy (p < 0.018), IDH1 status (p < 0.043), and TERT-p status (p < 0.014) were independently associated with OS. Our study demonstrates that patients with higher tumor histological grades who had received adjuvant radiotherapy exhibited IDH1-mut or presented with TERTp-wt experienced improved OS. Besides, an interesting finding showed an association between methylation of MGMTp and TERTp status with tumor location.

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Distribution and favorable prognostic implication of genomic EGFR alterations in IDH‐wildtype glioblastoma

et al. 2022

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Background We aimed to evaluate the mutation profile, transcriptional variants, and prognostic impact of the epidermal growth factor receptor ( EGFR ) gene in isocitrate dehydrogenase ( IDH )‐wildtype glioblastomas (GBMs). Methods We sequenced EGFR , evaluated the EGFR splicing profile using a next‐generation sequencing oncopanel, and analyzed the outcomes in 138 grade IV IDH ‐wildtype GBM cases. Results EGFR mutations were observed in 10% of GBMs. A total of 23.9% of the GBMs showed EGFR amplification. Moreover, 25% of the EGFR mutations occurred in the kinase domain. Notably, EGFR alterations were a predictor of good prognosis ( p = 0.035). GBM with EGFR alterations was associated with higher Karnofsky Performance Scale scores ( p = 0.014) and lower Ki‐67 scores ( p = 0.005) than GBM without EGFR alterations. EGFRvIII positivity was detected in 21% of EGFR ‐amplified GBMs. We identified two other EGFR variants in GBM cases with deletions of exons 6–7 (Δe 6–7) and exons 2–14 (Δe 2–14). In one case, the initial EGFRvIII mutation transformed into an EGFR Δe 2–14 mutation during recurrence. Conclusions We found that the EGFR gene profiles of GBM differ among cohorts and that EGFR alterations are good prognostic markers of overall survival in patients with IDH ‐wildtype GBM. Additionally, we identified rare EGFR variants with longitudinal and temporal transformations of EGFRvIII .

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Distribution and favorable prognostic implication of genomic EGFR alterations in IDH‐wildtype glioblastoma

Cited by 9 publications

References 49 publications

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

Genetic Prognostic Factors in Adult Diffuse Gliomas: A 10-Year Experience at a Single Institution

Distribution and favorable prognostic implication of genomic EGFR alterations in IDH‐wildtype glioblastoma

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