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Letter regarding Xiao WZ et al. entitled "Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis"

Dai W, Chen J, Guo X, Su Z

Tumour Biol., 2015 Jun;36(6):4089.
PMID: 26025112 DOI: 10.1007/s13277-015-3481-4

With great interest, we read the article "Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis" (by Xiao et al. Tumor Biol 35(7):6687-6693, 2014), which has reached important conclusions that the phosphatase and tensin homolog (PTEN) gene mutations were closely related to poor prognosis of glioma patients. Through quantitative analysis, the investigators (Xiao WZ et al.) showed that glioma patients with PTEN gene mutations exhibited a significantly shorter overall survival (OS) than those without PTEN gene mutations (HR = 3.66, 95 % CI = 2.02∼5.30, P glioma among Americans (HR = 3.72, 95 % CI = 1.72∼5.73, P 0.05). The meta-analysis results are encouraging. Nevertheless, some deficiencies still existed that we would like to raise.

Matched MeSH terms: Glioma/genetics*
Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis

Xiao WZ, Han DH, Wang F, Wang YQ, Zhu YH, Wu YF, et al.

Tumour Biol., 2014 Jul;35(7):6687-93.
PMID: 24705863 DOI: 10.1007/s13277-014-1885-1

We conducted a meta-analysis in order to investigate the relationships between PTEN gene mutations and the prognosis in glioma. The following electronic databases were searched for relevant articles without any language restrictions: Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013). Meta-analyses were conducted using the STATA software (Version 12.0, Stata Corporation, College Station, Texas USA). Hazard ratio (HR) with its corresponding 95 % confidence interval (95%CI) was calculated. Six independent cohort studies with a total of 357 glioma patients met our inclusion criteria. Our meta-analysis results indicated that glioma patients with PTEN gene mutations exhibited a significantly shorter overall survival (OS) than those without PTEN gene mutations (HR = 3.66, 95%CI = 2.02 ~ 5.30, P < 0.001). Ethnicity-stratified subgroup analysis demonstrated that PTEN gene mutations were closely linked to poor prognosis in glioma among Americans (HR = 3.72, 95%CI = 1.72 ~ 5.73, P < 0.001), while similar correlations were not observed among populations in Sweden, Italy, and Malaysia (all P > 0.05). Our meta-analysis provides direct and strong evidences for the speculation of PTEN gene mutations' correlation with poor prognosis of glioma patients.

Matched MeSH terms: Glioma/genetics*
Fulltext Mutations of the p53 gene in gliomas from Malay patients

Jafri A, Aziz MY, Ros S, Nizam I

Med J Malaysia, 2003 Jun;58(2):236-42.
PMID: 14569744

This is the first investigation performed to detect the presence of the p53 mutation in Malay patients with gliomas. The p53 gene was amplified using polymerase chain reaction (PCR) from 33 fresh-frozen tumour tissues from patients histologically confirmed as glioma. Four hot spot areas that lie between exon 5 to 8 were screened for mutation by mean of non-isotopic "cold" single strand conformation polymorphism (SSCP) analysis and direct sequencing. The frequency of p53 gene mutation in gliomas examined was 33% (11 of 33). Five (45.5%) cases had mutation in exon 7, four (36.4%) had mutation in exon 8 and two (18.1%) had mutation in exon 6. Seven (63.6%) of 11 mutations were single nucleotide point mutations of which 5 were missense mutations, 1 was nonsense mutation and 1 was, silent mutation. Three (27.3%) showed insertion mutation and 1 (9.1%) showed deletion mutation. Of the point mutations, 57.1% were transitions and 42.9% were transversions. These results suggested that p53 mutations frequently occur in gliomas and this gene does play an important role in the tumourigenesis process of Malay patients with brain tumours.

Matched MeSH terms: Glioma/genetics*
Molecular genetic analysis of phosphatase and tensin homolog and p16 tumor suppressor genes in patients with malignant glioma

Abdullah JM, Zainuddin N, Sulong S, Jaafar H, Isa MN

Neurosurg Focus, 2003 Apr 15;14(4):e6.
PMID: 15679305

Several genes have been shown to carry mutations in human malignant gliomas, including the phosphatase and tensin homolog (PTEN) deleted on chromosome 10 and p16 tumor suppressor genes. Alterations of this gene located on chromosome 10 q23 and 9p21, respectively, may contribute to gliomagenesis. In this study, the authors analyzed 20 cases of malignant gliomas obtained in patients living on the east coast of Malaysia to investigate the possibilities of involvement of the PTEN and p16 genes.

Matched MeSH terms: Glioma/genetics*
Fulltext Presence of allelic loss and PTEN mutations in malignant gliomas from Malay patients

Zainuddin N, Jaafar H, Isa MN, Abdullah JM

Med J Malaysia, 2004 Oct;59(4):468-79.
PMID: 15779579

Loss of heterozygosity (LOH) on several loci and mutations on PTEN tumor suppressor gene (10q23.3) occur frequently in sporadic gliomas. We have performed polymerase chain reaction (PCR)-LOH analysis using microsatellite markers and single-stranded conformational polymorphism (SSCP) analysis to determine the incidence of allelic losses on chromosome 10q, 9p, 17p and 13q and mutations of exons 5, 6 and 8 of the PTEN gene in malignant gliomas. Twelve of 23 (52.2%) malignant glioma cases showed allelic losses whereas 7 of 23, (30.4%) samples showed aberrant band patterns and mutations of the PTEN gene. Four of these cases showed LOH on 10q23 and mutations of the PTEN gene. The data on LOH indicated the involvement of different genes in gliomagenesis whereas mutations of the PTEN gene indicated the role of PTEN tumor suppressor gene in the progression of glioma in Malay population.

Matched MeSH terms: Glioma/genetics*
Fulltext Glioma-Derived miRNA-Containing Extracellular Vesicles Induce Angiogenesis by Reprogramming Brain Endothelial Cells

Lucero R, Zappulli V, Sammarco A, Murillo OD, Cheah PS, Srinivasan S, et al.

Cell Rep, 2020 02 18;30(7):2065-2074.e4.
PMID: 32075753 DOI: 10.1016/j.celrep.2020.01.073

Glioblastoma (GBM) is characterized by aberrant vascularization and a complex tumor microenvironment. The failure of anti-angiogenic therapies suggests pathways of GBM neovascularization, possibly attributable to glioblastoma stem cells (GSCs) and their interplay with the tumor microenvironment. It has been established that GSC-derived extracellular vesicles (GSC-EVs) and their cargoes are proangiogenic in vitro. To further elucidate EV-mediated mechanisms of neovascularization in vitro, we perform RNA-seq and DNA methylation profiling of human brain endothelial cells exposed to GSC-EVs. To correlate these results to tumors in vivo, we perform histoepigenetic analysis of GBM molecular profiles in the TCGA collection. Remarkably, GSC-EVs and normal vascular growth factors stimulate highly distinct gene regulatory responses that converge on angiogenesis. The response to GSC-EVs shows a footprint of post-transcriptional gene silencing by EV-derived miRNAs. Our results provide insights into targetable angiogenesis pathways in GBM and miRNA candidates for liquid biopsy biomarkers.

Matched MeSH terms: Glioma/genetics*
Critical role of HOX transcript antisense intergenic RNA (HOTAIR) in gliomas

Angelopoulou E, Paudel YN, Piperi C

J Mol Med (Berl), 2020 11;98(11):1525-1546.
PMID: 32978667 DOI: 10.1007/s00109-020-01984-x

Despite extensive research, gliomas are associated with high morbidity and mortality, mainly attributed to the rapid growth rate, excessive invasiveness, and molecular heterogeneity, as well as regenerative potential of cancer stem cells. Therefore, elucidation of the underlying molecular mechanisms and the identification of potential molecular diagnostic and prognostic biomarkers are of paramount importance. HOX transcript antisense intergenic RNA (HOTAIR) is a well-studied long noncoding RNA, playing an emerging role in tumorigenesis of several human cancers. A growing amount of preclinical and clinical evidence highlights the pro-oncogenic role of HOTAIR in gliomas, mainly attributed to the enhancement of proliferation and migration, as well as inhibition of apoptosis. In vitro and in vivo studies demonstrate that HOTAIR modulates the activity of specific transcription factors, such as MXI1, E2F1, ATF5, and ASCL1, and regulates the expression of cell cycle-associated genes along with related signaling pathways, like the Wnt/β-catenin axis. Moreover, it can interact with specific miRNAs, including miR-326, miR-141, miR-148b-3p, miR-15b, and miR-126-5p. Of importance, HOTAIR has been demonstrated to enhance angiogenesis and affect the permeability of the blood-tumor barrier, thus modulating the efficacy of chemotherapeutic agents. Herein, we provide evidence on the functional role of HOTAIR in gliomas and discuss the benefits of its targeting as a novel approach toward glioma treatment.

Matched MeSH terms: Glioma/genetics*
Fulltext Quantitative magnetic resonance imaging and radiogenomic biomarkers for glioma characterisation: a systematic review

Seow P, Wong JHD, Ahmad-Annuar A, Mahajan A, Abdullah NA, Ramli N

Br J Radiol, 2018 Dec;91(1092):20170930.
PMID: 29902076 DOI: 10.1259/bjr.20170930

OBJECTIVE:: The diversity of tumour characteristics among glioma patients, even within same tumour grade, is a big challenge for disease outcome prediction. A possible approach for improved radiological imaging could come from combining information obtained at the molecular level. This review assembles recent evidence highlighting the value of using radiogenomic biomarkers to infer the underlying biology of gliomas and its correlation with imaging features.
METHODS:: A literature search was done for articles published between 2002 and 2017 on Medline electronic databases. Of 249 titles identified, 38 fulfilled the inclusion criteria, with 14 articles related to quantifiable imaging parameters (heterogeneity, vascularity, diffusion, cell density, infiltrations, perfusion, and metabolite changes) and 24 articles relevant to molecular biomarkers linked to imaging.
RESULTS:: Genes found to correlate with various imaging phenotypes were EGFR, MGMT, IDH1, VEGF, PDGF, TP53, and Ki-67. EGFR is the most studied gene related to imaging characteristics in the studies reviewed (41.7%), followed by MGMT (20.8%) and IDH1 (16.7%). A summary of the relationship amongst glioma morphology, gene expressions, imaging characteristics, prognosis and therapeutic response are presented.
CONCLUSION:: The use of radiogenomics can provide insights to understanding tumour biology and the underlying molecular pathways. Certain MRI characteristics that show strong correlations with EGFR, MGMT and IDH1 could be used as imaging biomarkers. Knowing the pathways involved in tumour progression and their associated imaging patterns may assist in diagnosis, prognosis and treatment management, while facilitating personalised medicine.
ADVANCES IN KNOWLEDGE:: Radiogenomics can offer clinicians better insight into diagnosis, prognosis, and prediction of therapeutic responses of glioma.

Matched MeSH terms: Glioma/genetics
Fulltext Association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma: a meta-analysis

Xin Y, Hao S, Lu J, Wang Q, Zhang L

PLoS One, 2014;9(4):e95966.
PMID: 24763305 DOI: 10.1371/journal.pone.0095966

To comprehensively evaluate the association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma.

Matched MeSH terms: Glioma/genetics*
Fulltext Viability reduction and Rac1 gene downregulation of heterogeneous ex-vivo glioma acute slice infected by the oncolytic Newcastle disease virus strain V4UPM

Mustafa Z, Shamsuddin HS, Ideris A, Ibrahim R, Jaafar H, Ali AM, et al.

Biomed Res Int, 2013;2013:248507.
PMID: 23586025 DOI: 10.1155/2013/248507

Oncolytic viruses have been extensively evaluated for anticancer therapy because this virus preferentially infects cancer cells without interfering with normal cells. Newcastle Disease Virus (NDV) is an avian virus and one of the intensively studied oncolytic viruses affecting many types of cancer including glioma. Nevertheless, the capability of NDV infection on heterogeneous glioma tissue in a cerebrospinal fluid atmosphere has never been reported. Recently, Rac1 is reported to be required for efficient NDV replication in human cancer cells and established a link between tumourigenesis and sensitivity to NDV. Rac1 is a member of the Rho GTPases involved in the regulation of the cell migration and cell-cycle progression. Rac1 knockdown leads to significant inhibition of viral replication. In this work, we demonstrated that NDV treatment led to significant reduction of tumour tissue viability of freshly isolated heterogeneous human brain tumour slice, known as an ex vivo glioma acute slice (EGAS). Analysis of gene expression indicated that reduced tissue viability was associated with downregulation of Rac1. However, the viability reduction was not persistent. We conclude that NDV treatment induced EGAS viability suppression, but subsequent downregulation of Rac1 gene may reduce the NDV replication and lead to regrowth of EGAS tissue.

Matched MeSH terms: Glioma/genetics*
Molecular genetic analysis of BAX and cyclin D1 genes in patients with malignant glioma

Abdullah JM, Ahmad F, Ahmad KA, Ghazali MM, Jaafar H, Ideris A, et al.

Neurol Res, 2007 Apr;29(3):239-42.
PMID: 17509221

Brain tumorigenesis is a complex process involving multiple genetic alterations. Cyclin D1 and BAX genes are two of the most important regulators in controlling the normal proliferation and apoptosis of cells, respectively. In this study, we analysed the possibilities of involvement of cyclin D1 and BAX genes in the gliomagenesis.

Matched MeSH terms: Glioma/genetics*
Association of loss of heterozygosity and PTEN gene abnormalities with paraclinical, clinical modalities and survival time of glioma patients in Malaysia

Abdullah JM, Farizan A, Asmarina K, Zainuddin N, Ghazali MM, Jaafar H, et al.

Asian J Surg, 2006 Oct;29(4):274-82.
PMID: 17098662

The pattern of allelic loss of heterozygosity (LOH) and PTEN mutations appear to be associated with the progression of gliomas leading to a decrement in the survival rate of patients. This present study was carried out to determine the LOH and PTEN mutational status in glioma patients and its association with patients' survival.

Matched MeSH terms: Glioma/genetics*
Fulltext Prevalence of mitochondrial DNA common deletion in patients with gliomas and meningiomas: A first report from a Malaysian study group

Mohamed Yusoff AA, Mohd Khair SZN, Abd Radzak SM, Idris Z, Lee HC

J Chin Med Assoc, 2020 Sep;83(9):838-844.
PMID: 32732530 DOI: 10.1097/JCMA.0000000000000401

BACKGROUND: The 4977-bp common deletion (mtDNA) is a well-established mitochondrial genome alteration that has been described in various types of human cancers. However, to date, no studies on mtDNA in brain tumors have been reported. The present study aimed to determine mtDNA prevalence in common brain tumors, specifically, low- and high-grade gliomas (LGGs and HGGs), and meningiomas in Malaysian cases. Its correlation with clinicopathological parameters was also evaluated.
METHODS: A total of 50 patients with pathologically confirmed brain tumors (13 LGGs, 20 HGGs, and 17 meningiomas) were enrolled in this study. mtDNA was detected by using polymerase chain reaction (PCR) technique and later confirmed via Sanger DNA sequencing.
RESULTS: Overall, mtDNA was observed in 16 (32%) patients and it was significantly correlated with the type of tumor group and sex, being more common in the HGG group and in male patients.
CONCLUSION: The prevalence of mtDNA in Malaysian glioma and meningioma cases has been described for the first time and it was, indeed, comparable with previously published studies. This study provides initial insights into mtDNA in brain tumor and these findings can serve as new data for the global mitochondrial DNA mutations database.

Matched MeSH terms: Glioma/genetics*
Malignant glioma: the involvement of loss of allelic heterozygosity and PTEN mutations in a group of Malay patients

Zainuddin N, Jaafar H, Isa MN, Abdullah JM

Southeast Asian J Trop Med Public Health, 2005 May;36(3):748-56.
PMID: 16124450

Frequent loss of heterozygosity (LOH) and mutations of the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) have been found in sporadic gliomas. The most documented regions of allelic losses include 9p21, 10q23-25 and 17p1 3 whereas PTEN aberrations are preferentially found in glioblastoma multiformes. This research aimed to detect the incidence of allelic losses on chromosomes 10q, 9p, 17p and 13q and mutations on exons 5, 6 and 8 of PTEN in malignant gliomas. Malignant glioma specimens obtained were classified histopathologically according to the WHO criteria. Each tumor was then subjected to polymerase chain reaction (PCR)-LOH analysis using microsatellite markers and single-stranded conformational polymorphism (SSCP) analysis. Twelve of 23 (52%) malignant glioma cases showed allelic losses whereas 7 of 23 (30%) samples showed aberrant band patterns and mutations of PTEN. Four of these cases showed LOH in 10q23 and mutations of PTEN. The data on LOH indicated the involvement of different genes in the genesis of glioma whereas mutations of PTEN indicated the role of PTEN tumor suppressor gene in the progression of glioma in Malay population.

Matched MeSH terms: Glioma/genetics*
Genetic polymorphisms of EGF 5'-UTR and NAT2 857G/A associated with glioma in a case control study of Malaysian patients

Muthusamy KA, Lian LH, Vairavan N, Chua KH, Waran V

Genet. Mol. Res., 2012;11(3):2939-45.
PMID: 22782629

Studies of genetic mutations that have been used in predicting glioma prognosis have revealed a complex relationship between clinical and genetic factors. Epidermal growth factor (EGF) and the NAT2 gene play a central role in carcinogenesis. An adenine (A) to guanine (G) single nucleotide polymorphism at position 61 in the 5'-untranslated region (5'-UTR) of the EGF gene has been found to be associated with levels of EGF production, and the mutations in the NAT2 gene have been postulated as a risk factor for cancer. We investigated EGF and the NAT2 gene in 13 glioma tissue samples and 12 normal controls. In the EGF 5'-UTR 61G polymorphism, the heterozygote GA was the most common genotype in the glioma patients. In the NAT2 polymorphism at nucleotide position 857G/A, the G allele and the GG genotype were the most prevalent forms in both the glioma and normal samples. We did not find any homozygous AA genotypes in the glioma patients. Based on this preliminary evidence, the EGF 5'-UTR at position 61 and the NAT2 SNP at position 857 polymorphisms are associated with increased risk for glioma.

Matched MeSH terms: Glioma/genetics*
Fulltext A blood-based gene expression and signaling pathway analysis to differentiate between high and low grade gliomas

Ponnampalam SN, Kamaluddin NR, Zakaria Z, Matheneswaran V, Ganesan D, Haspani MS, et al.

Oncol Rep, 2017 Jan;37(1):10-22.
PMID: 28004117 DOI: 10.3892/or.2016.5285

The aims of the present study were to undertake gene expression profiling of the blood of glioma patients to determine key genetic components of signaling pathways and to develop a panel of genes that could be used as a potential blood-based biomarker to differentiate between high and low grade gliomas, non-gliomas and control samples. In this study, blood samples were obtained from glioma patients, non-glioma and control subjects. Ten samples each were obtained from patients with high and low grade tumours, respectively, ten samples from non-glioma patients and twenty samples from control subjects. Total RNA was isolated from each sample after which first and second strand synthesis was performed. The resulting cRNA was then hybridized with the Agilent Whole Human Genome (4x44K) microarray chip according to the manufacturer's instructions. Universal Human Reference RNA and samples were labeled with Cy3 CTP and Cy5 CTP, respectively. Microarray data were analyzed by the Agilent Gene Spring 12.1V software using stringent criteria which included at least a 2-fold difference in gene expression between samples. Statistical analysis was performed using the unpaired Student's t-test with a p<0.01. Pathway enrichment was also performed, with key genes selected for validation using droplet digital polymerase chain reaction (ddPCR). The gene expression profiling indicated that were a substantial number of genes that were differentially expressed with more than a 2-fold change (p<0.01) between each of the four different conditions. We selected key genes within significant pathways that were analyzed through pathway enrichment. These key genes included regulators of cell proliferation, transcription factors, cytokines and tumour suppressor genes. In the present study, we showed that key genes involved in significant and well established pathways, could possibly be used as a potential blood-based biomarker to differentiate between high and low grade gliomas, non-gliomas and control samples.

Matched MeSH terms: Glioma/genetics*
Loss of heterozygosity on chromosomes 10q, 9p, 17p and 13q in malays with malignant glioma

Zainuddin N, Jaafart H, Isa MN, Abdullah JM

Neurol Res, 2004 Jan;26(1):88-92.
PMID: 14977064

Recent advances in neuro-oncology have revealed different pathways of molecular oncogenesis in malignant gliomas including loss of heterozygosity on chromosomal regions harboring tumor suppressor genes. In the present study, we performed polymerase chain reaction-loss of heterozygosity (PCR-LOH) analysis using microsatellite markers to identify loss of heterozygosity on chromosomes 10q, 9p, 17p and 13q in the Malays with malignant gliomas. Of 12 cases with allelic losses, seven (58.3%) cases showed LOH on chromosome 10q, three (25.0%) cases showed LOH on chromosome 9p, four (33.3%) cases showed LOH on chromosome 17p and two (16.7%) cases showed LOH on chromosome 13q. The cases include five (41.7%) cases of glioblastoma multiforme, three (25.0%) cases of anaplastic astrocytoma, three (25.0%) cases of anaplastic oligodendroglioma and one (8.3%) case of anaplastic ependymoma. Four cases showed loss of heterozygosity on more than one locus. Our findings showed that loss of heterozygosity on specific chromosomal regions contributes to the molecular pathway of glioma progression in Malay population. In addition, these data provide useful evidence of molecular genetic alterations of malignant glioma in South East Asian patients, particularly in the East Coast of Malaysia.

Matched MeSH terms: Glioma/genetics*

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