Telomere maintenance and the etiology of adult glioma.
Walsh Kyle M,Wiencke John K,Lachance Daniel H,Wiemels Joseph L,Molinaro Annette M,Eckel-Passow Jeanette E,Jenkins Robert B,Wrensch Margaret R
A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length.
Polymorphisms in DNA Repair Gene and Susceptibility to Glioma: A Systematic Review and Meta-Analysis Based on 33 Studies with 15 SNPs in 9 Genes.
Liu Kun,Jiang Yugang
Cellular and molecular neurobiology
At present, many publications have evaluated the correlation between the DNA repair gene polymorphisms and glioma susceptibility. However, the results remain inconclusive. The aim of this research is to exhaustively assess the association of genetic polymorphisms in DNA repair genes with glioma risk in human. Meta-analysis method was conducted, and 33 studies with 15 SNPs in 9 genes were included (12553 glioma cases and 17178 controls). Correlation strength was evaluated by odds ratio with a 95 % confidence interval. Rs1799782 T allele and rs25487A allele might bring about higher risk of glioma in Asian population. Rs1805377 G allele was an increased risk genetic factor of glioma. Asian carried with rs3212986 A allele was more likely to have glioma. Rs1800067 G allele was a risk factor of developing glioma. Carriers with rs12917 CC genotype in MGMT gene had higher risk of glioma in Caucasian than other non-CC genotype carriers. Carriers with rs1136410 T allele in PARP1 gene could more likely to develop glioma in Caucasian. This meta-analysis suggests that glioma susceptibility is associated with rs1799782 and rs25487 of X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), rs1805377 of XRCC4, rs1800067 of excision repair cross-complementing rodent repair deficiency complementation group 4 (ERCC4) and rs3212986 of ERCC1 in Asian population, and rs12917 of O-6-methylguanine-DNA methyltransferase (MGMT) and rs1136410 of poly(ADP-ribose) polymerase 1 (PARP1) in Caucasian population.
Genetic and molecular epidemiology of adult diffuse glioma.
Molinaro Annette M,Taylor Jennie W,Wiencke John K,Wrensch Margaret R
Nature reviews. Neurology
The WHO 2007 glioma classification system (based primarily on tumour histology) resulted in considerable interobserver variability and substantial variation in patient survival within grades. Furthermore, few risk factors for glioma were known. Discoveries over the past decade have deepened our understanding of the molecular alterations underlying glioma and have led to the identification of numerous genetic risk factors. The advances in molecular characterization of glioma have reframed our understanding of its biology and led to the development of a new classification system for glioma. The WHO 2016 classification system comprises five glioma subtypes, categorized by both tumour morphology and molecular genetic information, which led to reduced misclassification and improved consistency of outcomes within glioma subtypes. To date, 25 risk loci for glioma have been identified and several rare inherited mutations that might cause glioma in some families have been discovered. This Review focuses on the two dominant trends in glioma science: the characterization of diagnostic and prognostic tumour markers and the identification of genetic and other risk factors. An overview of the many challenges still facing glioma researchers is also included.
Association between DNA repair gene polymorphisms and risk of glioma: a systematic review and meta-analysis.
Adel Fahmideh Maral,Schwartzbaum Judith,Frumento Paolo,Feychting Maria
BACKGROUND:Association studies of germline DNA repair single nucleotide polymorphisms (SNPs) and glioma risk have yielded inconclusive results. We therefore performed a systematic review and meta-analysis of studies investigating this association. METHODS:We identified 27 eligible studies investigating 105 SNPs in 42 DNA repair genes. Of these, 10 SNPs in 7 genes were analyzed in at least 4 studies and were therefore included in our meta-analysis. The meta-analysis was performed for homozygote comparison, heterozygote comparison, and dominant and recessive models by applying a fixed- or random-effects model. The funnel and forest plots were created using RevMan software. RESULTS:We found that SNPs rs3212986 (odds ratio [OR] = 1.35 (1.08-1.68), P = .008), rs13181 (OR = 1.18 (1.06-1.31), P = .002), and rs25487 (OR = 1.12 (1.03-1.22), P = .007) in DNA repair genes ERCC1, ERCC2 (XPD), and XRCC1 may increase the risk of glioma, while polymorphisms rs1136410 (OR = 0.78 (0.68-0.89), P = .0004) and rs12917 (OR = 0.84 (0.73-0.96), P = .01) in PARP1(ADPRT) and MGMT are associated with decreased susceptibility to glioma. No evidence of significant associations between ERCC2 rs1799793, OGG1 rs1052133, XRCC1 rs25489, XRCC1 rs1799782, or XRCC3 rs861539 and risk of glioma was observed. CONCLUSION:This study provides evidence that DNA repair genes ERCC1, ERCC2, and XRCC1 might be low-penetrance glioma-risk genes, while MGMT and PARP1 polymorphisms may confer protection against glioma.
Systematic review on the association between ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms and glioma risk.
Zhou C X,Zhao J H
Genetics and molecular research : GMR
Several studies have examined the association between excision repair cross-complementation group 1 (ERCC1) C8092A and ERCC2 Lys751Gln polymorphisms and glioma risk, but the results have been inconclusive. We conducted a meta-analysis of 12 studies to determine the association between ERCC1 rs3212986 and ERCC2 rs13181 genes and glioma susceptibility. We searched for relevant studies in both Chinese and English in PubMed, Web of Science, Cochrane Library, and EMBASE through January 1, 2014, and identified 3939 cases and 5407 controls. The results showed that individuals carrying the ERCC1 rs3212986 AA genotype had higher risk of glioma compared with the CC genotype, with a pooled odds ratio = 1.29, 95% confidence interval = 1.07-1.55. Subgroup analysis showed that the ERCC1 rs3212986 AA genotype was significantly associated with an increased risk of glioma in the Chinese population (odds ratio = 1.37, 95% confidence interval = 1.07-1.55), but no association in Caucasian Chinese. No significant association was observed between ERCC2 rs13181 polymorphisms and glioma risk. The results of our meta-analysis strongly suggested that the ERCC1 rs3212986 polymorphism was associated with a higher susceptibility to glioma, particularly in the Chinese population. Studies including a larger sample size and more specified information regarding pathological types of glioma are needed to confirm our results.
The role of the RTEL1 rs2297440 polymorphism in the risk of glioma development: a meta-analysis.
Zhang Cuiping,Lu Yu,Zhang Xiaolian,Yang Dongmei,Shang Shuxin,Liu Denghe,Jiang Kongmei,Huang Weiqiang
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
The regulator of the telomere elongation helicase1 (RTEL1) gene plays a crucial role in the DNA double-stand break-repair pathway by maintaining genomic stability. Recent epidemiological studies showed that the rs2297440 polymorphism in the RTEL1 gene was a potential risk locus for glioma development, but the results were inconclusive. To clarify the association between this polymorphism and the risk of glioma, we performed a comprehensive meta-analysis. The PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure databases were systematically searched to identify all relevant published studies up to 30 August 2015. Four eligible studies were finally included. The pooled results indicated that the RTEL1 rs2297440 polymorphism moderately increased the risk of glioma in all genetic models. A comparison of the dominant model CT + CC versus TT (OR 1.40; 95 % CI 1.24-1.60; p < 0.001) indicated that having the C allele conferred a 40 % increased risk of developing glioma. In a subgroup analysis based on geographic location (Europe, Asia, and America), there was an association between the rs2297440 polymorphism and the risk of glioma in all three areas. The results of the subgroup analysis based on source of control indicated an elevated risk of glioma in population-based control studies. This meta-analysis demonstrates that the RTEL1 rs2297440 polymorphism plays a moderate, but significant role in the risk of glioma. Further studies with larger sample sizes are necessary to confirm this finding.
Variations in Toll-like receptor and nuclear factor-kappa B genes and the risk of glioma.
Kına Idris,Sultuybek Gonul Kanigur,Soydas Tugba,Yenmis Guven,Biceroglu Huseyin,Dirican Ahmet,Uzan Mustafa,Ulutin Turgut
British journal of neurosurgery
PURPOSE:Glioblastoma (GBM) is the most aggressive primary brain tumour in the adult nervous system and is associated with a poor prognosis. NF-KB activation is an important driver of the malignant phenotype that confers a negative prognosis in patients with GBM. NF-KB plays a role in Toll-like Receptors (TLR)-induced tumourigenesis. The aim of the present study was to investigate the association of a promoter region polymorphism of NFKB1 gene encoding the p50 subunit of NF-KB, namely -94ins/del ATTG, the most widely discussed the TLR2 Arg753Gln, TLR4Asp299Gly and TLR4Thr399Ile polymorphisms, their combined effects, and the glioma risk. METHODS:A group of 120 Glioma patients and 225 control subjects were screened for these four polymorphisms using the PCR-RFLP method. RESULTS:Statistical analysis indicates that the ins/ins genotype of NFKB -94ins/delATTG (p=0.003), and the AA genotype of TLR4Asp299Gly (p < 0.001) are risk factors for glioma and people carrying the ins allele have an approximately 1.47 times susceptibility risk of glioma whereas GG genotype of TLR2Arg753Gln seems to be protective against glioma (p = 0.002). Combined genotype analysis showed that del/ins-GG genotype of TLR2Arg753Gln-NFKB1, del/ins + GG genotype of TLR4Asp299Gly-NFKB1, del/ins-CC genotype of TLR4Thr399Ile-NFKB1 were risk factors for glioma development. CONCLUSION:NFKB1 -94ins/delATTG and TLR4Asp299Gly polymorphisms are associated with increased glioma cancer risk in a Turkish population.