Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study

Späth, Florentin; Andersson, Ulrika; Dahlin, Anna M.; Langseth, Hilde; Hovig, Eivind; Johannesen, Tom Børge; Grankvist, Kjell; Björkblom, Benny; Wibom, Carl; Melin, Beatrice

doi:10.1007/s13277-015-4742-y

Cited by 8 publications

(7 citation statements)

References 43 publications

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“…One hypothesis of the link between genetic variants and the risk of subtype-specific disease could be that the genetic variants convey their increased glioma risk through contributing to a chronical activation of the EGFR receptor family that triggers tumor initiation. This is supported by the observation that glioma cases had higher concentrations of sEGFR and sERBB2 protein levels in prediagnostic serum samples from individuals that later developed GBM compared to matched controls [31,32]. In the brain tissue eQTL results, we found that risk variant of rs723527, located in intron 1, was associated with lower levels of EGFR expression.…”

Section: Idh-wildtype Glioma Risk Variantssupporting

confidence: 60%

The Genetic Architecture of Gliomagenesis–Genetic Risk Variants Linked to Specific Molecular Subtypes

Johansson

Wibom

et al. 2019

Cancers

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Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.

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Section: Idh-wildtype Glioma Risk Variantssupporting

confidence: 60%

The Genetic Architecture of Gliomagenesis–Genetic Risk Variants Linked to Specific Molecular Subtypes

Johansson

Wibom

et al. 2019

Cancers

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“…Another commonly noted feature of glioblastoma is the mutation and amplification of the EGFR gene [ 28 ]. The aberrant EGFR-mediated oncogenic signaling is found in glioblastoma [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Glioma exosomal microRNA-148a-3p promotes tumor angiogenesis through activating the EGFR/MAPK signaling pathway via inhibiting ERRFI1

Wang

Zhao

et al. 2020

Cancer Cell Int

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Background Glioma is the most frequent and lethal primary brain malignancy. Amounting evidence has highlighted the importance of exosomal microRNAs (miRNAs or miRs) in this malignancy. This study aimed to investigate the regulatory role of exosomal miR-148a-3p in glioma. Methods Bioinformatics analysis was firstly used to predict the target genes of miR-148a-3p. Exosomes were then extracted from normal human astrocytes and glioma cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to determine the expression patterns of miR-148a-3p and ERBB receptor feedback inhibitor 1 (ERRFI1). Dual-luciferase reporter gene assay was applied to verify the direct binding between miR-148a-3p and ERRFI1. Cell counting kit-8 and tube formation assays were further conducted to assess the proliferation and angiogenic properties of human umbilical vein endothelial cells (HUVECs) in the co-culture system with exosomes. Lastly, glioma tumor models were established in BALB/c nude mice to study the role of exosomal miR-148a-3p in vivo. Results miR-148a-3p was highly expressed, while ERRFI1 was poorly expressed in glioma. miR-148a-3p was found to be enriched in glioma cells-derived exosomes and could be transferred to HUVECs via exosomes to promote their proliferation and angiogenesis. ERRFI1 was identified as a target gene of miR-148a-3p. In addition, miR-148a-3p activated the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting ERRFI1. In the co-culture system, our data demonstrated that glioma cells-derived exosomal miR-148a-3p down-regulated ERRFI1 and activated the EGFR/MAPK signaling pathway, so as to promote cell proliferation and angiogenesis. In vivo experimentation further demonstrated that this mechanism was responsible for the promotive role of exosomal miR-148a-3p in tumorigenesis and angiogenesis. Conclusion Taken together, glioma-derived exosomal miR-148a-3p promoted tumor angiogenesis through activation of the EGFR/MAPK signaling pathway by ERRFI1 inhibition.

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“…Furthermore, several of the enriched pathways were associated with tumorigenesis, including ErbB, mTOR and cell cycle signaling pathways. The ErbB pathway is associated with tumor progression in the majority of cancer types, including glioma (36,37). Furthermore, Table II.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of microRNA‑374a predicts poor prognosis in human glioma

et al. 2019

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Certain microRNAs (miRNAs/miRs) may be used as prognostic biomarkers in various types of cancer. The purpose of the present study was to identify miRNAs that were abnormally expressed in glioma of different grades, and to evaluate their clinical implications in patients with glioma. The differentially expressed miRNAs were evaluated from the expression profiles of six glioma tissues (three low-grade and three high-grade gliomas) determined using a microarray platform. Reverse transcription-quantitative polymerase chain reaction analysis was used to further verify the aberrant expression of the candidate miRNA in a set of 42 patients and 5 healthy controls. The miRNA target genes were predicted and the protein-protein interaction network was generated; furthermore, functional enrichment analysis of the target genes in Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was performed. Kaplan-Meier curves and Log-rank analysis, as well as multivariate Cox regression analysis were performed to assess the association of the candidate miRNA with patient survival. A total of 15 differentially expressed miRNAs, including 13 downregulated and 2 upregulated miRNAs, were identified by comparison of low-grade and high-grade glioma tissues. The miR-374a expression of high-grade gliomas was significantly lower than that of low-grade gliomas (fold change, -4.43; P=0.027). The expression levels of miR-374a gradually decreased with the increase of the pathological grade of glioma. Pearson's Chi-square test was used to determine the association of miR-374a expression with several clinicopathological factors. Furthermore, low expression of miR-374a was determined to be an independent prognostic marker and that it was significantly associated with overall survival (P=0.0213). GO and KEGG pathway analysis revealed that the target genes of miR-374a may be involved in the regulation of the RNA polymerase II promoter and mTOR signaling pathway. The four hub genes (CCND1, SP1, CDK4, CDK6) were also identified by PPI network analysis. In conclusion, the present study indicated that miR-374a may be used as a promising prognostic biomarker for the screening of high-risk populations and for the assessment of the prognosis of patients with glioma.

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Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study

Cited by 8 publications

References 43 publications

The Genetic Architecture of Gliomagenesis–Genetic Risk Variants Linked to Specific Molecular Subtypes

The Genetic Architecture of Gliomagenesis–Genetic Risk Variants Linked to Specific Molecular Subtypes

Glioma exosomal microRNA-148a-3p promotes tumor angiogenesis through activating the EGFR/MAPK signaling pathway via inhibiting ERRFI1

Downregulation of microRNA‑374a predicts poor prognosis in human glioma

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