A troublesome burden, the amplification of EGFR in glioblastoma!
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ABSTRACT:
SUBMITTER: Lobbous M
PROVIDER: S-EPMC7229254 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glioblastoma (GBM), the most common malignant brain tumor in adults, contains a subpopulation of cells with a stem-like phenotype (GS-cells). GS-cells can be maintained in vitro using serum-free medium supplemented with epidermal growth factor, basic fibroblast growth factor-2, and heparin. However, this method does not conserve amplification of the Epidermal Growth Factor Receptor (EGFR) gene, which is present in over 50% of all newly diagnosed GBM cases. GS-cells with retained EGFR amplification could overcome the limitations of current in vitro model systems and contribute significantly to preclinical research on EGFR-targeted therapy. This review recapitulates recent methodological approaches to expand stem-like cells from GBM with different EGFR status in order to maintain EGFR-dependent intratumoral heterogeneity in vitro. Further, it will summarize the current knowledge about the impact of EGFR amplification and overexpression on the stem-like phenotype of GBM-derived GS-cells and different approaches to target the EGFR-dependent GS-cell compartment of GBM.
| S-EPMC4468289 | biostudies-other
Project description:Radiogenomics uses machine-learning (ML) to directly connect the morphologic and physiological appearance of tumors on clinical imaging with underlying genomic features. Despite extensive growth in the area of radiogenomics across many cancers, and its potential role in advancing clinical decision making, no published studies have directly addressed uncertainty in these model predictions. We developed a radiogenomics ML model to quantify uncertainty using transductive Gaussian Processes (GP) and a unique dataset of 95 image-localized biopsies with spatially matched MRI from 25 untreated Glioblastoma (GBM) patients. The model generated predictions for regional EGFR amplification status (a common and important target in GBM) to resolve the intratumoral genetic heterogeneity across each individual tumor-a key factor for future personalized therapeutic paradigms. The model used probability distributions for each sample prediction to quantify uncertainty, and used transductive learning to reduce the overall uncertainty. We compared predictive accuracy and uncertainty of the transductive learning GP model against a standard GP model using leave-one-patient-out cross validation. Additionally, we used a separate dataset containing 24 image-localized biopsies from 7 high-grade glioma patients to validate the model. Predictive uncertainty informed the likelihood of achieving an accurate sample prediction. When stratifying predictions based on uncertainty, we observed substantially higher performance in the group cohort (75% accuracy, n = 95) and amongst sample predictions with the lowest uncertainty (83% accuracy, n = 72) compared to predictions with higher uncertainty (48% accuracy, n = 23), due largely to data interpolation (rather than extrapolation). On the separate validation set, our model achieved 78% accuracy amongst the sample predictions with lowest uncertainty. We present a novel approach to quantify radiogenomics uncertainty to enhance model performance and clinical interpretability. This should help integrate more reliable radiogenomics models for improved medical decision-making.
| S-EPMC7886858 | biostudies-literature
Project description:Glioblastomas are the most frequent and aggressive primary brain tumors which are expressing various evolutions, aggressiveness, and prognosis. Thus, the 2007 World Health Organization classification based solely on the histological criteria is no longer sufficient. It should be complemented by molecular analysis for a true histomolecular classification. The new 2016 WHO classification of tumors of the central nervous system uses molecular parameters in addition to histology to reclassify these tumors and reduce the interobserver variability. The aim of this study is to determine the prevalence of IDH mutations and EGFR amplifications in the population of the northeast region of Morocco and then to compare the results with other studies. Methods. IDH1 codon 132 and IDH2 codon 172 were directly sequenced and the amplification of exon 20 of EGFR gene was investigated by qPCR in 65 glioblastoma tumors diagnosed at the University Hospital of Fez between 2010 and 2014. Results. The R132H IDH1 mutation was observed in 8 of 65 tumor samples (12.31%). No mutation of IDH2 was detected. EGFR amplification was identified in 17 cases (26.15%). Conclusion. A systematic search of both histological and molecular markers should be requisite for a good diagnosis and a better management of glioblastomas.
| S-EPMC5530437 | biostudies-other
Project description:Background: Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. Methods: In this work, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples (N = 40 patients, 20 with EGFR amplification). Results: In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. Conclusion: Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.
2023-01-25 | GSE222515 | GEO
Project description:Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. This cancer shows rapid, highly infiltrative growth, that invades individually or in small groups the surrounding tissue. The aggressive tumor biology of GBM has devastating consequences with a median survival of 15 months. GBM often has Epidermal Growth Factor Receptor (EGFR) abnormalities. Despite recent advances in the study of GBM tumor biology, it is unclear whether mutations in GBM are related to EGFR amplification and relevant phenotypes like tumor infiltration. This study aimed to perform whole-exome sequencing analysis in 30 human GBM samples for identifying mutational portraits associated with EGFR amplification and infiltrative patterns. Our results show that EGFR-amplified tumors have overall higher mutation rates than EGFR-no-amplified. Six genes out of 2029 candidate genes show mutations associated with EGFR amplification status. Mutations in these genes for GBM are novel, not previously reported in GBM, and with little presence in the TCGA database. GPR179, USP48, and BLK show mutation only in EGFR-amplified cases, and all the affected cases exhibit diffuse infiltrative patterns. On the other hand, mutations in ADGB, EHHADH, and PTPN13, were present only in the EGFR-no-amplified group with a more diverse infiltrative phenotype. Overall, our work identified different mutational portraits of GBM related to well-established features like EGFR amplification and tumor infiltration.
| S-EPMC8640814 | biostudies-literature
Project description:Background:We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification with or without variant III (EGFRvIII) deletion. Methods:Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO criteria) at 6 months (PFS6). Results:Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative Oncology Group Performance Status 0/1/2 were 10.2%/65.3%/24.5%, respectively. PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6 months and 3 patients were so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included 1 complete response and 2 partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs. Conclusions:Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.
| S-EPMC5737732 | biostudies-literature
Project description:We aimed to evaluate the preclinical efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), against glioblastoma (GBM) tumors using patient-derived xenograft (PDX) models. A total of 15 distinct GBM PDX models were used to evaluate the therapeutic efficacy of GC1118. Genomic data derived from PDX models were analyzed to identify potential biomarkers associated with the anti-tumor efficacy of GC1118. A patient-derived cell-based high-throughput drug screening assay was performed to further validate the efficacy of GC1118. Compared to cetuximab, GC1118 exerted comparable growth inhibitory effects on the GBM tumors in the PDX models. We confirmed that GC1118 accumulated within the tumor by crossing the blood-brain barrier in in vivo specimens and observed the survival benefit in GC1118-treated intracranial models. Genomic analysis revealed high EGFR amplification as a potent biomarker for predicting the therapeutic efficacy of GC1118 in GBM tumors. In summary, GC1118 exerted a potent anti-tumor effect on GBM tumors in PDX models, and its therapeutic efficacy was especially pronounced in the tumors with high EGFR amplification. Our study supports the importance of patient stratification based on EGFR copy number variation in clinical trials for GBM. The superiority of GC1118 over other EGFR mAbs in GBM tumors should be assessed in future studies.
| S-EPMC7693807 | biostudies-literature
Project description:Extensive infiltration of the surrounding healthy brain tissue is a critical feature in glioblastoma. Several miRNAs have been related to gliomagenesis, some of them related with the EGFR pathway. We have evaluated whole-genome miRNA expression profiling associated with different EGFR amplification patterns, studied by fluorescence in situ hybridization in tissue microarrays, of 30 cases of primary glioblastoma multiforme, whose clinicopathological and immunohistochemical features have also been analyzed. MicroRNA-200c showed a very significant difference between tumors having or not EGFR amplification. This microRNA plays an important role in epithelial-mesenchymal transition, but its implication in the behavior of glioblastoma is largely unknown. With respect to EGFR status our cases were categorized into three groups: high level EGFR amplification, low level EGFR amplification, and no EGFR amplification. Our results showed that microRNA-200c and E-cadherin expression are down-regulated, while ZEB1 is up-regulated, when tumors showed a high level of EGFR amplification. Conversely, ZEB1 mRNA expression levels were significantly lower in the group of tumors without EGFR amplification. Tumors with a low level of EGFR amplification showed ZEB1 expression levels comparable to those detected in the group with a high level of amplification. In this study we provide what is to our knowledge the first report of association between microRNA-200c and EGFR amplification in glioblastomas.
| S-EPMC4109944 | biostudies-literature
Project description:Epidermal growth factor receptor (EGFR) amplification and EGFR variant III (EGFRvIII, deletion of exons 2-7) are of clinical interest for glioblastoma. The aim was to develop a digital PCR (dPCR)-based method using locked nucleic acid (LNA)-based hydrolysis probes, allowing the simultaneous detection of the EGFR amplification and EGFRvIII variant. Sixty-two patients were included. An exploratory cohort (n?=?19) was used to develop the dPCR assay using three selected amplicons within the EGFR gene, targeting intron 1 (EGFR1), junction of exon 3 and intron 3 (EGFR2) and intron 22 (EGFR3). The copy number of EGFR was estimated by the relative quantification of EGFR1, EGFR2 and EGFR3 amplicon droplets compared to the droplets of a reference gene. EGFRvIII was identified by comparing the copy number of the EGFR2 amplicon to either the EGFR1 or EGFR3 amplicon. dPCR results were compared to fluorescence in situ hybridization (FISH) and next-generation sequencing for amplification; and to RT-PCR-based method for EGFRvIII. The dPCR assay was then tested in a validation cohort (n?=?43). A total of 8/19 EGFR-amplified and 5/19 EGFRvIII-positive tumors were identified in the exploratory cohort. Compared to FISH, the EGFR3 dPCR assay detected all EGFR-amplified tumors (8/8, 100%) and had the highest concordance with the copy number estimation by NGS. The concordance between RT-PCR and dPCR was also 100% for detecting EGFRvIII using an absolute difference of 10.8 for the copy number between EGFR2 and EGFR3 probes. In the validation cohort, the sensitivity and specificity of dPCR using EGFR3 probes were 100% for the EGFR amplification detection compared to FISH (19/19). EGFRvIII was detected by dPCR in 8 EGFR-amplified patients and confirmed by RT-PCR. Compared to FISH, the EGFR2/EGFR3 dPCR assay was estimated with a one-half cost value. These results highlight that dPCR allowed the simultaneous detection of EGFR amplification and EGFRvIII for glioblastoma.
| S-EPMC7165387 | biostudies-literature
Project description:Angiogenesis is regarded as a hallmark of cancer progression and it has been postulated that solid tumor growth depends on angiogenesis. At present, however, it is clear that tumor cell invasion can occur without angiogenesis, a phenomenon that is particularly evident by the infiltrative growth of malignant brain tumors, such as glioblastomas (GBMs). In these tumors, amplification or overexpression of wild-type (wt) or truncated and constitutively activated epidermal growth factor receptor (EGFR) are regarded as important events in GBM development, where the complex downstream signaling events have been implicated in tumor cell invasion, angiogenesis and proliferation. Here, we show that amplification and in particular activation of wild-type EGFR represents an underlying mechanism for non-angiogenic, invasive tumor growth. Using a clinically relevant human GBM xenograft model, we show that tumor cells with EGFR gene amplification and activation diffusely infiltrate normal brain tissue independent of angiogenesis and that transient inhibition of EGFR activity by cetuximab inhibits the invasive tumor growth. Moreover, stable, long-term expression of a dominant-negative EGFR leads to a mesenchymal to epithelial-like transition and induction of angiogenic tumor growth. Analysis of human GBM biopsies confirmed that EGFR activation correlated with invasive/non-angiogenic tumor growth. In conclusion, our results indicate that activation of wild-type EGFR promotes invasion and glioblastoma development independent of angiogenesis, whereas loss of its activity results in angiogenic tumor growth.
| S-EPMC3631314 | biostudies-literature