Molecular Epigenetics and Genetics in Neuro-Oncology

Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
Neurotherapeutics (Impact Factor: 5.05). 08/2009; 6(3):436-46. DOI: 10.1016/j.nurt.2009.04.002
Source: PubMed
Gliomas arise through genetic and epigenetic alterations of normal brain cells, although the exact cell of origin for each glioma subtype is unknown. The alteration-induced changes in gene expression and protein function allow uncontrolled cell division, tumor expansion, and infiltration into surrounding normal brain parenchyma. The genetic and epigenetic alterations are tumor subtype and tumor-grade specific. Particular alterations predict tumor aggressiveness, tumor response to therapy, and patient survival. Genetic alterations include deletion, gain, amplification, mutation, and translocation, which result in oncogene activation and tumor suppressor gene inactivation, or in some instances the alterations may simply be a consequence of tumorigenesis. Epigenetic alterations in brain tumors include CpG island hypermethylation associated with tumor suppressor gene silencing, gene-specific hypomethylation associated with aberrant gene activation, and genome-wide hypomethylation potentially leading to loss of imprinting, chromosomal instability, and cellular hyperproliferation. Other epigenetic alterations, such as changes in the position of histone variants and changes in histone modifications are also likely to be important in the molecular pathology of brain tumors. Given that histone deacetylases are targets for drugs that are already in clinical trial, surprisingly little is known about histone acetylation in primary brain tumors. Although a majority of epigenetic alterations are independent of genetic alterations, there is interaction on specific genes, signaling pathways and within chromosomal domains. Next-generation sequencing technology is now the method of choice for genomic and epigenome profiling, allowing more comprehensive understanding of genetic and epigenetic contributions to tumorigenesis in the brain.

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    • "The acquired methylation at the MGMT promoter results in silencing of the gene, which has been associated with prolonged survival in glioma patients, due to the enhanced susceptibility of tumor cells to the chemotherapeutic agents such as temozolomide [11, 12]. Besides MGMT, hypermethylation at the promoter of several tumor suppressors , apoptotic, or Wnt-signaling pathway involved genes and hypomethylation of normally silenced genes such as CD133, MMP9, or IL8 have also been identified among the glioma patients131415. Telomeres positioned at the ends of chromosomes are specialized nucleoprotein complexes containing multiple arrays of duplex TTAGGG repeats and a complex of telomere repeat binding proteins [16, 17]. Telomeres prevent degradation of chromosome (Chr.) "
    [Show abstract] [Hide abstract] ABSTRACT: Background Subtelomeric regions dynamically change their epigenetic pattern during development and progression of several malignancies and degenerative disorders. However, DNA methylation of human subtelomeres and their correlation to telomere length (TL) remain undetermined in glioma. Results Herein, we report on the selective changes in subtelomeric DNA methylation at the end of five chromosomes (Chr.) (7q, 8q. 18p, 21q, and XpYp) and ascertain their correlation with TL in patients with glioma. Subtelomeric methylation level was invariably higher in glioma patients compared to the control group, irrespective of their age and tumor grade. In particular, a significant increase in methylation was observed at the subtelomeric CpG sites of Chr. 8q, 21q, and XpYp in tissues, obtained from the brain tumor of glioma patients. In contrast, no significant change in methylation was observed at the subtelomere of Chr. 7q and 18p. Selective changes in the subtelomeric methylation level, however, did not show any significant correlation to the global TL. This observed phenomenon was validated in vitro by inducing demethylation in a glioblastoma cell line (SF-767) using 5-azacytidine (AZA) treatment. AZA treatment caused significant changes in the subtelomeric methylation pattern but did not alter the TL, which supports our hypothesis. Conclusions DNA methylation level dramatically increased at the subtelomere of Chr.8q, 21q, and XpYp in malignant glioma, which could be used as an early epigenetic diagnostic biomarker of the disease. Alterations in subtelomeric methylation, however, have no effects on the TL.
    Full-text · Article · Oct 2015 · Clinical Epigenetics
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    • "They could act as tumor‑specific biomarkers and can be detected in a sample by methylation‑sensitive polymerase chain reaction (PCR). [18,47,49] "
    [Show abstract] [Hide abstract] ABSTRACT: A brain tumor is an intracranial neoplasm within the brain or in the central spinal canal. Primary malignant brain tumors affect about 200,000 people worldwide every year. Brain cells have special characters. Due to the specific properties of brain tumors, including epidemiology, growth, and division, investigation of brain tumors and the interpretation of results is not simple. Research to identify the genetic alterations of human tumors improves our knowledge of tumor biology, genetic interactions, progression, and preclinical therapeutic assessment. Obtaining data for prevention, diagnosis, and therapy requires sufficient samples, and brain tumors have a wide range. As a result, establishing the bank of brain tumors is very important and essential.
    Full-text · Article · Jan 2015
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    • "The diversity in the pathogenesis and clinical characteristics of glioblastoma among Uyghur and Han patients indicates the presence of certain differences at the genetic level between these 2 ethnic groups. In this study, based on retrospective analysis and follow-up studies of the clinical characteristics of glioblastoma among Uyghur and Han patients, as well as the molecular-level changes in high-grade glioma [3], we used mRNA expression profiling to screen for differential gene markers of glioblastoma among Uyghur and Han patients. Our goal was to compare the differences in gene expression in glioblastoma and to preliminarily investigate the differences in pathogenesis between these 2 ethnic groups. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The aim of this study was to investigate differences in glioblastoma RNA gene expression profiles between Uyghur and Han patients in Xinjiang province and to screen and compare differentially expressed genes with respect to their clinical significance in the pathogenesis of high-grade glioma and their relationship to disease prognosis. Material and methods: Illumina HT-12mRNA expression profiles microarray was employed to measure the gene expression profiles of 6 patients with advanced glioma and to screen for differentially expressed genes. Results: GO and KEGG analyses were performed on the differentially expressed genes using Web Gestalt software (P<0.05). Comparison of glioblastoma RNA expression profiles in the Uyghur and Han patients indicated that 1475 genes were significantly differentially expressed, of which 669 showed increased expression, while 807 showed decreased expression. One gene (STRC) corresponded to 2 transcripts, 1 of which showed increased expression and the other showed decreased expression. The differentially expressed genes participate in metabolic processes, biological regulation, stress response, and multi-cellular organic processes, including small GTPase regulatory signaling pathways, Ras signaling pathway, neuronal reactive protein regulation, and myelination of the central nervous system. The genes are also involved in tumor-related signaling pathways, including metabolic pathways, cancer pathways, MAPK signaling pathway, TGF-β signaling pathway, neurotrophic factor signal transduction pathway, and mTOR signaling pathway. Conclusions: Differentially expressed genes were screened by studying the gene expression profiles in glioblastoma from Uyghur and Han patients. The cellular function and location of these genes were further investigated. Based on related molecular markers of glioblastoma, the differences in the mechanism of initiation and development of glioblastoma between Uyghur and Han patients were investigated for polygenic interactions.
    Preview · Article · Nov 2014 · Medical science monitor: international medical journal of experimental and clinical research
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