No association of (−131C→G) variant of CHI3L1 gene with risk of glioblastoma and prognosis (original) (raw)
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High CHI3L1 expression is associated with glioma patient survival
Background: Survival of glioma patients with the same tumor histology and grade can vary significantly, and some low-grade gliomas transform to a more malignant phenotype. There is a need of molecular signatures, which are better predictors of the patient diagnosis, outcome of treatment, and prognosis than the diagnosis provided by histopathology. We propose CHI3L1 mRNA expression as a prognostic biomarker for patients with glioma. Methods: We measured CHI3L1 expression with quantitative real time-polymerase chain reaction (qRT-PCR) in the cohort of 98 patients with different grade glioma: 10 grade I pylocytic astrocytomas, 30 grade II diffuse astrocytomas, 20 grade III anaplastic astrocytomas, and 38 grade IV astrocytomas (glioblastomas). Statistical analyses were conducted to investigate the association between CHI3L1 mRNA expression levels and patient clinical variables.
Gene Encoding Chitinase 3-Like 1 Protein (CHI3L1) is a Putative Oncogene
International journal of biomedical science : IJBS, 2011
An important task in understanding oncogenesis is the identification of those genes whose copy number and expression increase during tumorigenesis. Previously, in an effort to identify genes which could be used as molecular markers for glial tumors, we compared gene expression in glioblastoma to the normal brain cells. Among the genes with the most pronounced increased expression in tumors there was CHI3L1, encoding the secreted chitinase 3-like 1 protein (also known as HC gp-39 or YKL-40). Expression of CHI3L1 was found increased significantly in various tumors in comparison with corresponding normal tissues. Here we show that CHI3L1 can decrease the doubling time of 293 cells. We have also demonstrated that CHI3L1 allows the anchorage-independent growth in soft agar and, in addition, stable CHI3L1 expression made 293 cells tumorigenic: these cells stimulate the initiation of tumors after their xenograft transplantation into the Wistar rat brains. Thus, the overexpression of CHI3L1 is likely to be critical in the development of some tumors and when we gain more information about mechanisms of CHI3L1 oncogenicity, it could be used as one of the potential targets for anticancer therapy. (Int J Biomed Sci 2011; 7 (3): 230-237)
Genetic secrets of long term glioblastoma survivors20190626 87134 5lm9eu
Bosnian Journal of Basic Medical Sciences, 2019
Glioblastomas are the most aggressive and lethal primary astrocytic tumors of the central nervous system. They account for 60% to 70% of all gliomas and the majority are diagnosed in Caucasian male patients at advanced age. Genetic analyses of glioblastoma show a great intra- and inter-tumor heterogeneity, which opens up a debate about its cellular origin. Different types of brain cells, including astrocytes, neural stem cells, oligodendrocyte precursor cells and glioblastoma stem cells are proposed to have a role in tumor initiation and spreading; however, data is still inconclusive. Due to short life expectancy, long-term glioblastoma survivors are defined as patients who live longer than two years post-diagnosis. Extreme survivors, living 10 years or more after diagnosis, comprise less than 1% of all patients. Molecular testing indicates genetic differences between short- and long-term survivors with glioblastoma. The most informative are IDH1/2 gene mutations and MGMT promoter methylation, which are associated with a better response to standard clinical care. Moreover, a decreased expression of the CHI3L1, FBLN4, EMP3, IGFBP2, IGFBP3, LGALS3, MAOB, PDPN, SERPING1 and TIMP1 genes has been associated with prolonged survival. In addition, emerging evidence suggests the role of different microRNAs in predicting patient survival. Other factors that may affect the survival of glioblastoma patients include clinical/demographic characteristics such as seizures at presentation, age at diagnosis, and the extent of surgical resection. Because of the small number of long-term survivors with glioblastoma, comparative studies on genetic differences between short- and long-term survivors are challenging. To improve patient management and clinical outcomes, a thorough "omics" approach is necessary for identifying differences between short- and long-term survivors with glioblastoma.
Journal of Neuro-Oncology, 2016
During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.
Genetic secrets of long-term glioblastoma survivors
Genetic secrets of long-term glioblastoma survivors, 2019
Glioblastomas are the most aggressive and lethal primary astrocytic tumors of the central nervous system. They account for 60% to 70% of all gliomas and the majority are diagnosed in Caucasian male patients at advanced age. Genetic analyses of glioblastoma show a great intra- and inter-tumor heterogeneity, which opens up a debate about its cellular origin. Different types of brain cells, including astrocytes, neural stem cells, oligodendrocyte precursor cells and glioblastoma stem cells are proposed to have a role in tumor initiation and spreading; however, data is still inconclusive. Due to short life expectancy, long-term glioblastoma survivors are defined as patients who live longer than two years post-diagnosis. Extreme survivors, living 10 years or more after diagnosis, comprise less than 1% of all patients. Molecular testing indicates genetic differences between short- and long-term survivors with glioblastoma. The most informative are IDH1/2 gene mutations and MGMT promoter methylation, which are associated with a better response to standard clinical care. Moreover, a decreased expression of the CHI3L1, FBLN4, EMP3, IGFBP2, IGFBP3, LGALS3, MAOB, PDPN, SERPING1 and TIMP1 genes has been associated with prolonged survival. In addition, emerging evidence suggests the role of different microRNAs in predicting patient survival. Other factors that may affect the survival of glioblastoma patients include clinical/demographic characteristics such as seizures at presentation, age at diagnosis, and the extent of surgical resection. Because of the small number of long-term survivors with glioblastoma, comparative studies on genetic differences between short- and long-term survivors are challenging. To improve patient management and clinical outcomes, a thorough “omics” approach is necessary for identifying differences between short- and long-term survivors with glioblastoma.
Prognostic stratification of patients with anaplastic gliomas according to genetic profile
Cancer, 2006
BACKGROUND.There is a need to improve the current, controversial, and poorly reproducible classification of anaplastic gliomas, which represent a highly heterogeneous entity in terms of survival.There is a need to improve the current, controversial, and poorly reproducible classification of anaplastic gliomas, which represent a highly heterogeneous entity in terms of survival.METHODS.The impact of the most common genetic alterations on survival was investigated based on 156 anaplastic gliomas: Among the patients who were included, the gender ratio was 1.32, the median age was 45.5 years (range, 20–83 years), and the median Karnofsky performance status was 70 (range, 40–100). Genetic analysis included a search for loss of heterozygosity (LOH) on chromosomes 1p and 19q; amplification of chromosomes 9p and 10q and of the epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4) and mouse double-minute (MDM2) genes; and p53 expression.The impact of the most common genetic alterations on survival was investigated based on 156 anaplastic gliomas: Among the patients who were included, the gender ratio was 1.32, the median age was 45.5 years (range, 20–83 years), and the median Karnofsky performance status was 70 (range, 40–100). Genetic analysis included a search for loss of heterozygosity (LOH) on chromosomes 1p and 19q; amplification of chromosomes 9p and 10q and of the epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4) and mouse double-minute (MDM2) genes; and p53 expression.RESULTS.The median survival was 33.5 months, and the median progression-free survival was 15.8 months. In a univariate analysis, LOH on 1p and 19q was correlated with longer survival, whereas p53 expression, LOH on 9p, LOH on 10q, amplified EGFR, and deleted CDKN2A were correlated with shorter survival. LOH on 1p and 19q were associated with oligodendrogliomas, LOH on 10q was related to EGFR amplification, and LOH on 1p and 19q was mutually exclusive with EGFR amplification and LOH on 10q. In a multivariate analysis, the significant prognostic factors were age, histology, LOH on 1p and 19q, and P16/CDKN2A deletion. Recursive partitioning analysis (RPA) divided the whole group hierarchically into 3 distinct prognostic subgroups: Group A with 1p19q codeletion (median survival, 98 months), Group B with EGFR amplification (median survival, 17 months), and Group CC (median survival, 31 months), providing a basis for a genetically based prognostic subclassification for patients with Grade III gliomas.The median survival was 33.5 months, and the median progression-free survival was 15.8 months. In a univariate analysis, LOH on 1p and 19q was correlated with longer survival, whereas p53 expression, LOH on 9p, LOH on 10q, amplified EGFR, and deleted CDKN2A were correlated with shorter survival. LOH on 1p and 19q were associated with oligodendrogliomas, LOH on 10q was related to EGFR amplification, and LOH on 1p and 19q was mutually exclusive with EGFR amplification and LOH on 10q. In a multivariate analysis, the significant prognostic factors were age, histology, LOH on 1p and 19q, and P16/CDKN2A deletion. Recursive partitioning analysis (RPA) divided the whole group hierarchically into 3 distinct prognostic subgroups: Group A with 1p19q codeletion (median survival, 98 months), Group B with EGFR amplification (median survival, 17 months), and Group CC (median survival, 31 months), providing a basis for a genetically based prognostic subclassification for patients with Grade III gliomas.CONCLUSIONS.The search for 1p19q codeletion and EGFR receptor amplification provides a simple, clinically relevant prognostic subclassification of grade III gliomas. Cancer 2006. © 2006 American Cancer Society.The search for 1p19q codeletion and EGFR receptor amplification provides a simple, clinically relevant prognostic subclassification of grade III gliomas. Cancer 2006. © 2006 American Cancer Society.
Neuro-oncology, 2010
Despite the increasing knowledge about the genetic alterations and molecular pathways involved in gliomas, few studies have investigated the association between the gene expression profiles (GEP) and both cytogenetics and histopathology of gliomas. Here, we analyzed the GEP (U133Plus2.0 chip) of 40 gliomas (35 astrocytic tumors, 3 oligodendrogliomas, and 2 mixed tumors) and their association with tumor cytogenetics and histopathology. Unsupervised and supervised analyses showed significantly different GEP in low-vs high-grade gliomas, the most discriminating genes including genes involved in the regulation of cell proliferation, apoptosis, DNA repair, and signal transduction. In turn, among glioblastoma multiforme (GBM), 3 subgroups of tumors were identified according to their GEP, which were closely associated with the cytogenetic profile of their ancestral tumor cell clones: (i) EGFR amplification, (ii) isolated trisomy 7, and (iii) more complex karyotypes. In summary, our results show a clear association between the GEP of gliomas and tumor histopathology; additionally, among grade IV astrocytoma, GEP are significantly associated with the cytogenetic profile of the ancestral tumor cell clone. Further studies in larger series of patients are necessary to confirm our observations.
Neuro-Oncology, 2012
Background. Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) at 7 loci influencing glioma risk: rs2736100 (TERT), rs11979158 and rs2252586 (EGFR), rs4295627 (CCDC26), rs4977756 (CDKN2A/CDKN2B), rs498872 (PHLDB1), and rs6010620 (RTEL1). Materials and methods. We studied the relationship among these 7 glioma-risk SNPs and characteristics of tumors from 1374 patients, including grade, IDH (ie IDH1 or IDH2) mutation, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, 9p and 10q loss, and 1p-19q codeletion. Results. rs2736100 (TERT) and rs6010620 (RTEL1) risk alleles were associated with high-grade disease, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, and 9p and 10q deletion; rs4295627 (CCDC26) and rs498872 (PHLDB1) were associated with low-grade disease, IDH mutation, and 1p-19q codeletion. In contrast, rs4977756 (CDKN2A/B), rs11979158 (EGFR), and to a lesser extent, rs2252586 (EGFR) risk alleles were independent of tumor grade and genetic profile. Adjusting for tumor grade showed a significant association between rs2736100 and IDH status (P ¼ .01), 10q loss (P ¼ .02); rs4295627 and 1p-19q codeletion (P ¼ .04), rs498872 and IDH (P ¼ .02), 9p loss (P ¼ .04), and 10q loss (P ¼ .02). Case-control analyses stratified into 4 molecular classes (defined by 1p-19q status, IDH mutation, and EGFR amplification) showed an association of rs4295627 and rs498872 with IDH-mutated gliomas (P , 10 23) and rs2736100 and rs6010620 with IDH wild-type gliomas (P , 10 23 and P ¼ .03). Conclusion. The frequency of EGFR and CDKN2A/B risk alleles were largely independent of tumor genetic profile, whereas TERT, RTEL1, CCDC26, and PHLDB1 variants were associated with different genetic profiles that annotate distinct molecular pathways. Our findings provide further insight into the biological basis of glioma etiology.
From reverse transcription to human brain tumors
Biopolymers and Cell, 2013
Reverse transcriptase from avian myeloblastosis virus (AMV) was the subject of the study, from which the investigations of the Department of biosynthesis of nucleic acids were started. Production of AMV in grams quantities and isolation of AMV reverse transcriptase were established in the laboratory during the seventies of the past century and this initiated research on the cDNA synthesis, cloning and investigation of the structure and functions of the eukaryotic genes. Structures of salmon insulin and insulin-like growth factor (IGF) family genes and their transcripts were determined during long-term investigations. Results of two modern techniques, microarray-based hybridization and SAGE, were used for the identification of the genes differentially expressed in astrocytic gliomas and human normal brain. Comparison of SAGE results on the genes overexpressed in glioblastoma with the results of microarray analysis revealed a limited number of common genes. 105 differentially expressed genes, common to both methods, can be included in the list of candidates for the molecular typing of glioblastoma. The first experiments on the classification of glioblastomas based on the data of the 20 genes expression were conducted by using of artificial neural network analysis. The results of these experiments showed that the expression profiles of these genes in 224 glioblastoma samples and 74 normal brain samples could be according to the Kohonen's maps. The CHI3L1 and CHI3L2 genes of chitinase-like cartilage protein were revealed among the most overexpressed genes in glioblastoma, which could have prognostic and diagnostic potential. Results of in vitro experiments demonstrated that both proteins, CHI3L1 and CHI3L2, may initiate the phosphorylation of ERK1/ ERK2 and AKT kinases leading to the activation of MAPK/ERK1/2 and PI3K/AKT signaling cascades in human embryonic kidney 293 cells, human glioblastoma U87MG, and U373 cells. The new human cell line 293_CHI3L1, stably producing chitinase-like protein CHI3L1 was developed and these cells were found to have an accelerated growth rate and could undergo anchorage-independent growth in soft agar which is one of the most consistent indicators of oncogenic transformation. The formation of tumors in rats by 293_CHI3L1 cells evidences that CHI3L1 is an oncogene involved in tumorigenesis. In vitro experiments showed that constitutive expression of CHI3L1 gene promotes chromosome instability in 293 cells.