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Published on: September 13, 2022
Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse
Petar Brlek1, Anja Kafka1,2, Anja Bukovac1,2
1Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.
Abstract:
Diffuse gliomas are a heterogeneous group of tumors with aggressive biological behavior and a lack of effective treatment methods. Despite new molecular findings, the differences between pathohistological types still require better understanding. In this in silico analysis, we investigated AKT1, AKT2, AKT3, CHUK, GSK3β, EGFR, PTEN, and PIK3AP1 as participants of EGFR-PI3K-AKT-mTOR signaling using data from the publicly available cBioPortal platform. Integrative large-scale analyses investigated changes in copy number aberrations (CNA), methylation, mRNA transcription and protein expression within 751 samples of diffuse astrocytomas, anaplastic astrocytomas and glioblastomas. The study showed a significant percentage of CNA in PTEN (76%), PIK3AP1 and CHUK (75% each), EGFR (74%), AKT2 (39%), AKT1 (32%), AKT3 (19%) and GSK3β (18%) in the total sample. Comprehensive statistical analyses show how genomics and epigenomics affect the expression of examined genes differently across various pathohistological types and grades, suggesting that genes AKT3, CHUK and PTEN behave like tumor suppressors, while AKT1, AKT2, EGFR, and PIK3AP1 show oncogenic behavior and are involved in enhanced activity of the EGFR-PI3K-AKT-mTOR signaling pathway. Our findings contribute to the knowledge of the molecular differences between pathohistological types and ultimately offer the possibility of new treatment targets and personalized therapies in patients with diffuse gliomas.
Insights
This study reveals distinct molecular profiles of diffuse gliomas, identifying specific genes like AKT3, CHUK, and PTEN as tumor suppressors and others like AKT1, AKT2, and EGFR as oncogenes, paving the way for targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Diffuse gliomas are aggressive brain tumors with poorly understood molecular differences.
- Effective treatment strategies are limited, highlighting the need for deeper molecular insights.
Purpose of the Study:
- To investigate the roles of key genes in the EGFR-PI3K-AKT-mTOR pathway in diffuse gliomas.
- To analyze genomic and epigenomic alterations across different glioma pathohistological types and grades.
Main Methods:
- In silico analysis of 751 diffuse glioma samples using cBioPortal data.
- Investigated copy number aberrations (CNA), methylation, mRNA, and protein expression of selected genes.
- Performed comprehensive statistical analyses to correlate molecular changes with glioma types.
Main Results:
- High frequencies of CNA observed in PTEN (76%), PIK3AP1 (75%), CHUK (75%), and EGFR (74%).
- Identified AKT3, CHUK, and PTEN as potential tumor suppressors.
- Highlighted AKT1, AKT2, EGFR, and PIK3AP1 as oncogenes driving the EGFR-PI3K-AKT-mTOR pathway.
Conclusions:
- Genomic and epigenomic alterations significantly impact gene expression in diffuse gliomas.
- Distinct molecular signatures identified across glioma pathohistological types.
- Findings offer potential for novel therapeutic targets and personalized treatment strategies for diffuse gliomas.
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