|Year : 2016 | Volume
| Issue : 4 | Page : 125-129
The progress in molecular biomarkers of gliomas
Jing Qi1, Hongwei Yang2, Xin Wang2, Yanyang Tu1
1 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
2 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
|Date of Submission||26-Jul-2016|
|Date of Acceptance||17-Aug-2016|
|Date of Web Publication||26-Aug-2016|
Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, Shaanxi
Source of Support: None, Conflict of Interest: None
Malignant glioma, a common form of central nervous system tumor, has a poor prognosis. The overall survival of these patients is as low as 12–14 months only. In general, the progress in personal precision medication has been gradually directed toward the molecular profiling of the tumors. Malignant glioma is one such tumor in which treatment response relies largely on its molecular characteristics, thus making the understanding of these markers essential to deliver the best treatment possible. Representative molecular markers (isocitrate dehydrogenase 1 mutation, 1p19q codeletion, epidermal growth factor receptor variant III amplification, human telomerase reverse transcriptase promoter mutations, alpha thalassemia/mental retardation syndrome X-linked mutation, and O-methylguanine DNA methyltransferase promoter methylation) are described/discussed in this article. Furthermore, the research prospects of cell-free DNA, regarded as a new developing trend of molecular markers, are discussed. There is an immense hope in these promising molecular markers which are expected to improve the overall survival and quality of life of malignant glioma patients.
Keywords: Glioblastoma, molecular markers, therapeutic strategies
|How to cite this article:|
Qi J, Yang H, Wang X, Tu Y. The progress in molecular biomarkers of gliomas. Cancer Transl Med 2016;2:125-9
| Introduction|| |
With its incidence rate almost accounting for 50%, glioma is the most common form of primary central nervous system tumors. The overall survival, after diagnosis, of glioma patients is as low as 12–14 months. Based on the involved cell types, gliomas are classified as oligodendroglioma, astrocytoma, ependymoma, medulloblastoma, and mixed glioma. The highly invasive character of gliomas, without obvious boundaries with respect to normal tissue around the tumor, makes its complete surgical resection hard to accomplish. Thus, specialists recommend a combination therapy, including surgery, chemotherapy, and radiation therapy, to delay the recurrence and prolong survival.,,, Chemotherapy and radiation therapy target the cells in their growth phase but fail to affect the quiescent glioma stem cell. This is why invasive glioma has a low cure rate and a high recurrence rate, despite the combination therapy. However, recently, immunotherapy has shown promise in treating such devastating disease. A deeper understanding of the specific molecular markers is the core part of such immunotherapy, which we have attempted to discuss here.
| Isocitrate Dehydrogenase Encoding Gene Mutation|| |
Isocitrate dehydrogenase (IDH), one of the key factors in metabolism, encodes IDH that catalyzes the oxidative decarboxylation process, producing α-ketoglutarate and CO2. Its two variants, IDH1 and IDH2, use NADP + as a cofactor to catalyze the reaction. IDH mutations exist in more than 70% of low-grade and malignant gliomas.,, The most common mutation is seen in IDH1 variant (over 95%) which occurs at R132H, which is a single amino acid residue of the IDH1 active site. This results in a loss of the enzyme's ability to catalyze the conversion of isocitrate to α-ketoglutarate, and instead the IDH1 mutant results in catalyzing α-ketoglutarate to 2-hydroxy glutaric acid, which is associated with hereditary hypertension, cancer, metabolic genetic instability, and malignant transformation. Since IDH1 mutation is the most common and earliest genetic changes in glioma, it serves as an early biomarker in diagnosis and prognosis of glioma patients. Li et al. found that glioma patients with IDH1 mutations had higher level of pyruvate carboxylase than glioma patients without IDH1 mutations. Esmaeili et al. showed that IDH1-R132H mutations affect ethanolamine phosphate and glycerol phosphate, choline, and phospholipid metabolism in glioma.
Forced expression of IDH1 mutation in astrocytes stimulates methylation in G-CIMP-positive low-grade gliomas. Duncan et al. found that IDH1 mutation is the molecular basis of G-CIMP phenotype, which emphasizes the importance of carcinogenesis and aid in the development of epigenetics-based treatment strategies. Schumacher et al. found that CD4+ Th1 cells and antibodies occur spontaneously in IDH1-R132H glioma patients and a vaccine targeting IDH1-R132H exhibit potent mutation-specific antitumor immune response.
IDH mutations had been associated to glioma prognosis,,, with the IDH1/2-mutated patients exhibiting favorable prognosis and longer survival duration.,, Further, the IDH mutations are negatively correlated to the tumor grade; IDH mutation rates of Class II, III, and IV level glioma were 77%, 55%, and 6% respectively. The mutations are also positively correlated with therapeutic response of the patient.
| 1p19qcodeletion|| |
1p19q codeletion occurs at the long arm of chromosome 19 (19q) and the short arm of chromosome 1 (1p) in gliomas. Allelic loss in 1p has been found in gliomas with a major oligodendroglial component; grade II oligodendrogliomas, grade III anaplastic oligodendrogliomas, and grade II to III mixed oligoastrocytomas. The incidence of allelic loss in 19q is particularly high in oligodendroglial tumors (81%) and mixed gliomas (31%). More than 75% of tumors with allelic deletion in 19q also exhibited a loss of heterozygosity in loci in 1p. Chemotherapy of the 25 glioma patients with temozolomide (TMZ) found that the response rate of patients with 1p19q codeletion was better than patients without the same. After treating with TMZ, the growth rate of tumor (in diameter) in patients with 1p19q codeletion was smaller than the other patients. The patients with 1p19q codeletion showed more relapse or less relapse after TMZ therapy. It is shown that 1p19q codeletion may delay the development of resistance to TMZ.,
Currently, the 1p19q codeletion, in combination with other markers, is used to evaluate the prognosis and treatment response of glioma patients. 1p19q codeletion and O -methylguanine DNA methyltransferase (MGMT) promoter methylation are independent positive prognostic markers. Furthermore, 1p19q deletion also exhibits IDH mutations. Combined IDH mutation, MGMT promoter methylation, and 1p19q codeletion greatly increased patient survival rates.,
In addition, 1p19q codeletion is an important indicator of the prognosis and chemosensitivity of low-grade gliomas. Among the oligodendroglioma and grade II glioblastoma patients, 5-year survival rates of patients with 1p19q codeletion were significantly higher than patients without the same.,
| Epidermal Growth Factor Receptor Variant Iii Amplification|| |
Epidermal growth factor belongs to receptor tyrosine kinase (RTK) family, a membrane receptor superfamily, with intrinsic protein tyrosine kinase activity. In glioblastoma, a relatively specific mutation of epidermal growth factor (EGFR), called EGFR variant III (EGFRvIII), is often observed. Mutations, amplifications, or misregulations of EGFR family members are involved in about 30% of all epithelial cancers. Constitutively active mutant EGFRvIII is present in 25–30% of malignant glioma patients with EGFR amplification/overexpression., EGFRvIII gene subtypes were identified in 12 of 22 samples and were accompanied by a lack of p53 mutation. A study also found that the expression of G-CIMP phenotype led to the repression of EGFR signaling.
EGFRvIII plays a role in tumorigenesis by activating other RTK. Greenall et al. demonstrated that EGFRvIII activity in U87MG glioma cells is directly proportional to the MET transactivation. The simultaneous targeting of both EGFRvIII and transactivated RTKs, resulted in significantly better survival of the test subjects in a mouse model, indicating that blocking both transactivated RTK and EGFRvIII may be an effective treatment strategy for EGFRvIII-positive glioma condition.
O-Methylguanine Dna Methyltransferase Promoter Hypermethylation
MGMT is a ubiquitous DNA repair enzyme which plays an important role in resisting cellular DNA damage induced by alkylating agents (e.g. TMZ), by directly removing the alkyl group from the O -atom of guanine. This process does not require other cofactors, as the MGMT protein acts as a methyltransferase and methyl acceptor for MGMT inactivation during methylation. Clinical trials have proved that MGMT promoter methylation is a positive prognostic marker that renders tumors more sensitive to radiation therapy. Substantial evidence also shows that MGMT methylation level is a positive predictive marker for the responsiveness of newly diagnosed glioma to alkylating agents.,, Further, two prospective randomized phase III clinical trials reported that MGMT promoter methylation status plays a predictive role in elderly patients who receive TMZ treatment., The TMZ chemotherapeutic sensitivity of glioma patients with MGMT promoter methylation was found to be higher than those without MGMT promoter methylation, and thus it was reported as a sign for higher TMZ chemotherapeutic sensitivity and better prognosis.
| Human Telomerase Reverse Transcriptase Promoter Mutations|| |
Human telomerase maintains the telomere length at the ends of chromosomes maintaining the cells ability of active division. Human telomerase is a ribonucleoprotein enzyme consisting of human telomerase reverse transcriptase (hTERT), human telomerase RNA component, and human telomerase-associated protein 1, where hTERT is the catalytic subunit of telomerase. A variation in the telomere maintenance is seen in most of the tumors. TERT promoter mutation occurs mainly in 124 and 146 bp upstream of the transcription start site. These mutations will enhance TERT promoter activity. One study showed that the mutations in TERT promoter will enhance the expression levels of telomerase and its activity. After the tumor genetic analysis, the researchers found that about 70–80% of primary glioblastoma and 70% of oligodendroglioma had TERT promoter mutations. The hTERT promoter mutation finding is of concern as it is an early finding in progressive glioblastoma.,
Findings from the brain tumor study indicate that glioblastoma patients with TERT promoter mutations has shorter overall survival rates  and exhibited a negative correlation with degree of glioma malignancy. TERT promoter mutations also showed a negative correlation with IDH1 and TP53 mutation while it was positively correlated with EGFR amplification. These mutations are useful in predicting the life span and prognosis of glioma patients; the median survival time of Grade III–IV glioma patients with IDH mutation, TERT mutation, or IDH + TERT mutation had a median survival time of 57, 11.5, or 125 months, respectively.
| Alpha Thalassemia/Mental Retardation Syndrome X-Linked Gene Mutation|| |
The proteins encoded by alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene are chromatin remodeling proteins, which form stable protein complexes with DAXX (death-domain associated protein) to interplay with histone H3.3 assembling chromatin and telomeres. ATRX mutations results in telomere maintenance through telomere-independent pathway, leading to indefinite dividing of cells.
The difference between ARTX and TERT promoter mutation is that the ARTX mutation is associated with no telomerase activity, whereas TERT promoter mutation is associated with enhanced telomerase activity. ATRX mutations in gliomas occur mainly in the Grade II–III astrocytomas, oligodendroglioma, and secondary glioblastomas, whereas TERT promoter mutation is seen mainly in primary glioblastoma and oligodendroglioma. Moreover, the presence of both IDH and ATRX mutations in glioma can be considered as the pathological diagnosis of astrocytoma.,
| Other Markers|| |
There are few other markers related to the prognosis of patients with glioma. NF1 mutations frequently occur in mesenchymal subtypes. Ozawa et al. found that NF1 deletions may render neuronal precursor tumors into mesenchymal subtypes. Increased expression of Myc is seen in 60–80% of gliomas and its expression level has been associated with the grading of the condition. Increased activity of the Myc gene plays an important role in neuronal differentiation of glioblastoma initiation cells, in addition to promoting their self-renewal ability.,
Further, in diffuse intrinsic pontine gliomas, recurrent somatic mutations of the activin receptor gene, ACVR1, were identified by combining whole-genome, whole-exome, methylome sequencing, and transcriptome. These mutations result in constitutively activated proteins, which lead to the phosphorylation of SMAD and the overexpression of its downstream targets, inhibitor of DNA binding protein 1 and 2 (ID1/2). In pediatric midline high-grade astrocytomas, a gain-of-function mutation in ACVR1 leads to the hyperactivation of bone morphogenetic protein (BMP)-ACVR1 pathway, resulting in increased phosphorylation of SMAD 1/5/8, and the activation of BMP target genes. In brain-stem gliomas, tumor-specific mutations in PPM1D were identified by targeted mutational analysis and exome sequencing. Being the high-frequency target of somatic mutation, PPM1D mutations enhance the cell's capacity to inhibit the activation of DNA damage response, making it a potential target in brain stem glioma treatment.
| Conclusion|| |
Identifying the molecular characteristics of the glioma regulation network may increase the precision of personalized medication. The integrity of circulating cell-free (cfDNA) in serum or plasma appears to be of diagnostic and prognostic value in cancer. During apoptosis and necrosis of cancer cells, cfDNA is released into the tumor microenvironment. The size of 70–200 bp cfDNA fragment ranges from small to the large fragment of approximately 21 kb. The half-life of cfDNA varies from 5 min to several hours, as these fragments are quickly and effectively cleared in liver and kidney. Thus, cfDNAs are perfect targets for biopsies as they reflect disease progression and turnover in real time.,,
There is no single molecular marker that can reveal the condition of all gliomas. Future studies on glioma biomarkers must focus on the identification of specific associated molecules while improving the sensitivity of their detection along with the feasibility of the procedure. To better understand biological characteristics of glioma tumor, comprehensive analysis of the associated multiple molecular markers should be performed. However, biopsy has not timely reacted the state of the tumor due to the existence of heterogeneity. Despite all the advances, accurate and comprehensive diagnosis of glioma is still not feasible, thus keeping the challenge open for future studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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