|Year : 2015 | Volume
| Issue : 5 | Page : 176-180
Genetic Characteristics of Glioblastoma: Clinical Implications of Heterogeneity
Qian Li1, Yanyang Tu2
1 Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
2 Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, China
|Date of Submission||16-Apr-2015|
|Date of Acceptance||14-Aug-2015|
|Date of Web Publication||29-Oct-2015|
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
Source of Support: None, Conflict of Interest: None
Glioblastoma multiforme (GBM) is a heterogeneous group of tumors, each with its own distinct molecular and genetic signatures. This heterogeneity is a major clinical hurdle for classifying tumors and for devising effective personalized therapies targeting the disease pathways. Herein, the primary genetic and epigenetic alterations in GBM that have been used as therapeutic targets in clinical settings nowadays, with or without clinical benefits for patients, as well as the future directions for developing novel strategies were discussed.
Keywords: Glioblastoma multiforme, molecular profiling, targeted therapy
|How to cite this article:|
Li Q, Tu Y. Genetic Characteristics of Glioblastoma: Clinical Implications of Heterogeneity. Cancer Transl Med 2015;1:176-80
| Introduction|| |
Glioblastoma multiforme (GBM) is the most common and fatal adult brain tumor, accounting for 60–70% of all gliomas. Despite the advances in the treatment options, the median survival time for patients with GBM is approximately 15 months. GBM is divided into primary and secondary glioblastoma based on their clinical characteristics. The primary glioblastoma progresses rapidly and has an absence of precursor lesions while secondary glioblastoma progresses as diffuse astrocytoma (WHO Grade II) or anaplastic astrocytoma (WHO Grade III).,, Recent investigations on genetic profile of GBM have revealed some "single biomarkers" useful in diagnostic and prognostic assessments, such as isocitrate dehydrogenase-1 (IDH1) mutations, which are frequently detected in secondary glioblastoma (> 80%) but are rare in primary glioblastoma (< 5%).,,,, The Cancer Genome Atlas More Details (TCGA) research described a molecular classification of GBM, based on its gene expression, into proneural, neural, classical, and mesenchymal subtypes  and also updated the knowledge of distinct genomic alterations between primary and secondary glioblastoma [Table 1].
|Table 1: The distinct genetic and clinical characteristics between primary and secondary glioblastoma|
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| Molecular Heterogeneity|| |
Recently, the comprehensive large-scale genomic analyses have identified intratumoral heterogeneity of GBM to further refine the histopathological classification of this disease. The TCGA have shown genetic and epigenetic alterations in GBM and revealed its potential prognostic or diagnostic biomarkers such as TP53 mutation, IDH1 mutation, epidermal growth factor receptor (EGFR) amplification/mutation, and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation.,
Intratumoral molecular heterogeneity is a clinical and therapeutical challenge in fighting tumor recurrence and invasion. To understand this challenge, we can look at the two extensively used targeted therapies: Targeting EGFR or vascular endothelial growth factor inhibitors. Such targeted therapies end up affecting a subpopulation of tumor cells that actively express the respective proteins but do not influence the rest of the tumor cells which continue to proliferate through a selection phase. Gene expression profiling has shown distinct molecular and genetic aberrations involved in tumorigenesis ,, of GBM and is subclassified accordingly to match the standard subclassification. Verhaak et al. proposed four molecular subtypes featuring distinct genetic, epigenetic, and transcriptional alterations, including proneural, neural, classical, and mesenchymal, which are accepted for their prognostic and diagnostic value. The examples of such molecular subtypes are IDH1/2 mutation for proneural, EGFR amplification for classical and neurofibromin 1 (NF1) loss for mesenchymal. EGFR amplification, IDH1/2 mutations, and hypermethylation of the promoter of the MGMT gene, together with co-deletion of 1p and 19q serve as the primary detection biomarkers.
| Molecular Biomarkers|| |
Epidermal growth factor receptor amplification/variants
EGFR is the most common therapeutic target in glioblastoma with the prevalence of its gene amplification in 40–60% of patients.,, EGFR alterations subsequently activate multiple cell signaling pathways and ultimately accelerates tumor growth and progression. The most common EGFR mutant variant is EGFRvIII, which is a constitutive activation of EGFR in a ligand-independent way and has a controversial prognostic impact. EGFRvIII variant has been found not related to patient outcome, associated with unfavorable prognosis, or as a molecular predictor for prolonged overall survival. The attempts to block EGFR signaling by small molecule inhibitors, such as erlotinib and gefitinib, or monoclonal antibodies could not get the desired results, even after molecular preselection of patients. Accordingly, the mechanisms underlying resistance to EGFR-targeted therapies and prognostic value of EGFR amplification or its variants remain to be clarified.
Isocitrate dehydrogenase-1/isocitrate dehydrogenase-2 mutations
Both IDH1 and IDH2 mutations are more frequently detected among Grade II to III gliomas and secondary glioblastoma (70–75%), whereas they are rare in primary glioblastoma (5%)., IDH1 mutations are strongly associated with TP53 mutation and deletion of 1p/19q. IDH1 mutations are typically present in younger patients with TP53 mutations and are associated with a better outcome. IDH1/2 mutations are also strongly associated with epigenetic alterations., IDH mutation together with 1p/19q co-deletion and glioma-CpG island hypermethylator phenotype (G-CIMP) are recognized as the prognostic criterion of a favorable outcome and also as a predictor of chemotherapy response.,
O(6)-Methylguanine-DNA methyltransferase promoter methylation
MGMT encodes a DNA repair enzyme involved in repairing the cytotoxic adducts produced by alkylating chemotherapy using temozolomide. Hypermethylation or epigenetic silencing of MGMT disables DNA repair capacity and render tumor cells more sensitive to treatment. MGMT promoter methylation is a common feature in IDH1/2 mutant/G-CIMP positive glioma; however, it is less prevalent in G-CIMP negative tumors, such as primary glioblastoma.,,
Neurofibromin 1 loss
NF1 gene encodes NF1, which is a tumor suppressor and negatively regulates RAS and mammalian target of rapamycin (mTOR) signaling in astrocytomas.,, NF1 mutations are the most common characteristics of mesenchymal GBM subtype. Inactivation of NF1 protein may arise from increased degradation, mediated by hyperactivation of protein kinase C., NF1 loss could cause increased cell proliferation and migration through hyperactivation of mTOR, mediated by RAS signaling pathway, in NF1-deficient primary murine astrocytes. Although the homozygous loss of NF1 results in increased cell growth, both under in vitro and in vivo conditions, it alone is inadequate for inducing tumor formation in genetically engineered mouse models. Several studies, using genetically engineered mouse models, have shown that the homozygous loss of NF1 in glial cells results in malignant astrocytomas when associated with a TP53 mutation  and further progress to GBM when combined with phosphatase and tensin homologue deletion.
Platelet-derived growth factor receptor alpha amplification
Platelet-derived growth factor receptor alpha (PDGFRA) gene is amplified in approximately 13% of GBMs, mainly in a proneural subtype of GBM., Amplification of PDGF and PDGFR is proved to be associated with aggressive glioma growth. PDGFR and/or its ligands expression lead to tumor development through both autocrine and paracrine signaling mechanisms., In addition, PDGFR can also be activated in the absence of its ligand. An intragenic deletion in PDGFRA, termed PDGFRA Δ,, is found to be associated with increased downstream c-Jun phosphorylation in a ligand-independent manner. Point mutations are detected exclusively in Grade IV gliomas, which suggests that PDGFRA-targeted therapy could be a promising therapeutic target for these patients.
| Clinical Implications of Heterogeneity|| |
Intratumoral heterogeneity serves two purposes in clinical settings: One as a prognostic and predictive biomarker to guide personalized treatments, and the other as a failure factor in targeted therapies. Among genetic alterations in GBM, majority exists in three signaling pathways including RTK/RAS/PI3K, p53/MDM2/MDM4, and RB/CDK4/INK4A. Several common targeted treatments in clinical trials are shown in [Table 2]. However, targeted agents such as bevacizumab have shown minimal efficacy in clinical trials and overall survival compared to the current standard of care remain poor., The combination of diversity of tumor subclones, poor drug penetration, and activation of other compensatory pathways contribute to this failure.,
In conclusion, identification of subtypes and novel markers such as IDH1 are promising addition to traditional histopathological grading for improving prognostic and predictive ability. However, because of the limitations in diagnostic approaches added with the complex changes during tumor progression, the response to therapy may not be intrinsically predictable, yet. The concept of personalized treatment to meet the clinical needs is still a long way to go. The combined treatment with multiple inhibitors of different pathways or treatments using agents targeting the regulatory molecules may be a promising future direction for a successful GBM treatment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]
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