Molecular and Genomic Alterations in Glioblastoma Multiforme
Open accessAbstract
In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types. This translates into well-defined genomic profiles that have been recently classified by The Cancer Genome Atlas Consortium into four subtypes: classic, mesenchymal, proneural, and neural GBM. Herein, we review the most relevant genetic alterations of primary versus secondary GBM, the specific signaling pathways involved, and the overall genomic profile of this genetically heterogeneous group of malignant tumors.
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Amplification of MDM2 and MDM4 can inactivate p53, leading to loss of tumor suppressor functions including growth arrest, apoptosis, DNA repair, and senescence.
“Amplification of MDM2 and MDM4 can inactivate p53, leading to loss of various tumor suppressor functions including growth arrest, apoptosis, DNA repair, and senescence [27,41].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [41]
The Growth Factor TKR Pathways section reports MDM2 and MDM4 amplification in glioblastoma and describes their regulation of TP53. It also links TP53 to cell-cycle arrest, DNA repair, and cell death, but our copy does not identify senescence as a function lost through this pathway. Page numbers are not available in the indexed passages. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMDM2 targets p53 for degradation, acting as a negative regulator.
“MDM2 targets p53 for degradation, acting as a negative regulator [27,41].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [41]
According to The Cancer Genome Atlas, MDM2 and MDM4 amplifications are found in 14% and 7% of glioblastomas, respectively.
“According to the TCGA, MDM2 and MDM4 amplifications are found in 14% and 7% of GBMs, respectively [41].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [41]
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References 101 · Cited by 225
Research works printed but not linked: 1
- Somasundaram K, Reddy SP, Vinnakota K, Britto R, Subbarayan M, Nambiar S, Hebbar A, Samuel C, Shetty M, Sreepathi HK, ajp.amjpathol.org -The American Journal of Pathology
- Authors
- Crespo, I., Vital, A. L., Gonzalez-Tablas, M., Patino, M. D. C., Otero, A., Lopes, M. C., de Oliveira, C., Domingues, P., Orfao, A., & Tabernero, M. D.
- Affiliations
- Universidad de Salamanca (ES)
- University of Coimbra (PT)
- ORCID
- Lopes, María Celeste
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 185
- Issue
- 7
- Pages
- 1820-1833
- ISSN
- 0002-9440 (ISSN-L)
- OpenAlex
- W1497063493
- Cited by
- 225
- References
- 101
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 27 · 2023: 21 · 2022: 16 · 2021: 19 · 2020: 25 · 2019: 24 · 2018: 23 · 2017: 17 · 2016: 19 · 2015: 3
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- FCT (SFRH/BD/64799/2009)
- IECSCYL
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- glioblastoma, genetic alterations, molecular classification, EGFR amplification, IDH1/2 mutation, TP53 mutation, Ras signaling, PI3K/Akt signaling, retinoblastoma pathway, genomic subtypes, TCGA, neurogenesis
- MeSH terms
- Animals, Brain Neoplasms, Glioblastoma, Humans, Mutation, Signal Transduction, Genomics, Mice, Epigenomics
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