Tumor Biol. DOI 10.1007/s13277-014-1684-8
RESEARCH ARTICLE
Regulator of telomere elongation helicase 1 (RTEL1) rs6010620 polymorphism contribute to increased risk of glioma Wei Zhao & Yusong Bian & Wei Zhu & Peng Zou & Guotai Tang
Received: 30 December 2013 / Accepted: 22 January 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Regulator of telomere elongation helicase 1 (RTEL1) is critical for genome stability and tumor avoidance. Many studies have reported the associations of RTEL1 rs6010620 with glioma risk, but individually published results were inconclusive. This meta-analysis was performed to quantitatively summarize the evidence for such a relationship. The PubMed, Embase, and Web of Science were systematically searched to identify relevant studies. The odds ratio (OR) and 95 % confidence interval (95 % CI) were computed to estimate the strength of the association using a fixed or random effects model. Ten studies were eligible for meta-analysis including data on glioma with 6,490 cases and 9,288 controls. Overall, there was a significant association between RTEL1 rs6010620 polymorphism and glioma risk in all four genetic models (GG vs. AA: OR = 1.87, 95 % CI = 1.60–2.18, Pheterogeneity =0.552; GA vs. AA: OR=1.30, 95 % CI=1.16– 1.46, Pheterogeneity =0.495; dominant model—GG+GA vs. AA: OR=1.46, 95 % CI=1.31–1.63, Pheterogeneity =0.528; recessive model—GG vs. GA+AA: OR=1.36, 95 % CI=1.27– 1.46, Pheterogeneity =0.093). Subgroup analyses by ethnicity showed that RTEL1 rs6010620 polymorphism resulted in a higher risk of glioma among both Asians and Caucasians. In the stratified analysis by ethnicity and source of controls, significantly increased risk was observed for Asians and Europeans in all genetic models, population-based studies in all genetic models, and hospital-based studies in three genetic models (heterozygote comparison, homozygote comparison, and dominant model). Our meta-analysis suggested that
Wei Zhao and Yusong Bian contributed equally to this study, and they should be regarded as joint first authors. W. Zhao : Y. Bian : W. Zhu : P. Zou (*) : G. Tang (*) Department of Neurosurgery, Yuhuangding Hospital of Yantai, 20 Yuhuangding East Road, Yantai 264000, Shandong, China e-mail: [email protected] e-mail: [email protected]
RTEL1 rs6010620 polymorphism is likely to be associated with increased glioma risk, which lends further biological plausibility to these findings. Keywords Cancer . Meta-analysis . Polymorphism . RTEL1 Abbreviations RTEL1 Regulator of telomere elongation helicase 1 OR Odds ratio CI Confidence interval HWE Hardy–Weinberg equilibrium PB Population-based HB Hospital-based
Introduction Gliomas that originate from glial cells surrounding and supporting neurons are the most common primary tumors of the central nervous system (CNS), accounting for the vast majority (80 %) of malignant primary brain tumors (PBT) [1–4]. Although the etiology of glioma remains unclear, exposure to moderate- to high-doses of ionizing radiation may be the only contributing factor identified currently [1, 5–7]. However, this only explains a small proportion of cases, suggesting that other causes, including genetic susceptibility, might play a pivotal role in modifying glioma occurrence. DNA repair and telomere maintenance are essential for genomic stability. Regulator of telomere elongation helicase 1 (RTEL1), a DNA helicase crucial for regulation of telomere length, has been shown to contribute to genome maintenance, both at telomeres and at sites of mitotic DNA damage as well as promoting meiotic synthesis-dependent strand annealing [8–11]. In the absence of RTEL1, shortened telomere length, chromosome breaks, and translocations were observed,
Tumor Biol.
demonstrating the possibility that RTEL1 protein may function to protect the genome against instability [8, 12, 13]. Furthermore, RTEL1-depleted mice died between days 10 and 11.5 of gestation, having severe defects that involve multiple organs including the nervous system, vasculature, heart, and extraembryonic tissues [8]. Upregulation of RTEL1 may be a critical event that accelerates the onset of liver carcinogenesis, gastrointestinal tract tumors, and breast cancers in mammals [14–18]. It has been demonstrated that human RTEL1 genomic locus (20q13.3) was amplified in approximately 30 % of gliomas with copy number change correlating with RTEL1 expression [19]. Together, inappropriate RTEL1 expression cells will undergo uncontrolled homologous recombination and result in telomere loss or gain and chromosomal translocations and rearrangements, all of which could drive genome instability and tumorigenesis. Single nucleotide polymorphisms (SNPs), the most common type of sequence variations in the human genome, contribute to human phenotypic differences [20]. RTEL1 gene locates in chromosome 20q13.3 with the length of 40.889 kb, including 40 exons. Rs6010620 maps to intron 12 of the RTEL1 and locates within a 65-kb region of linkage disequilibrium at 20q13.33 [12]. Recently, a number of studies have reported the role of this SNP and glioma risk, but the results are inconclusive [19, 21–24]. Meta-analysis is a powerful concept and tool which is directed toward the quantitative integration of findings from various studies. In the present study, we carried out a meta-analysis including subgroup analysis on all eligible case-control studies to derive a more precise estimation of the association between RTEL1 rs6010620 polymorphism and glioma risk. Heterogeneity, publication bias, and sensitivity analysis were also explored.
Materials and methods Publication search We searched electronic databases PubMed, Embase, and Web of Science (last search was updated on 10 Oct 2013). The following search terms were used in isolation and combination with one another: “RTEL1 OR rs6010620” AND “polymorphism OR variant or mutation” AND “glioma” using the limits, Humans, English, Cancer. The related reference articles of original studies on this topic were checked for other relevant articles. All studies matching the eligible criteria were included in our meta-analysis. Inclusion criteria Eligible studies included in our meta-analysis have to meet all the following criteria: (a) evaluation of the association
between RTEL1 rs6010620 polymorphism and glioma risk, (b) use a case-control design, and (c) sufficient data for estimating odds ratios (ORs) with their 95 % confidence interval (CI). Articles that were not about cancer research, contained duplicated previous research, or did not include usable genotype data were excluded. Data extraction Two investigators independently extracted the necessary data from all eligible publications and reached a consensus on all items. For each study, the following information was collected: the name of first author, year of publication, country origin, ethnicity (European or Asian), cancer type, source of controls (population- or hospital-based controls or mixed (composed of both population- and hospital-based controls)), total number of cases and controls, numbers of cases and controls with RTEL1 rs6010620 polymorphism genotypes, G allele frequency in controls, and P value for Hardy– Weinberg equilibrium. Statistical methods The departure from the Hardy–Weinberg equilibrium for the control group in each study was assessed with Pearson’s goodness-of-fit chi-square test with 1 degree of freedom. The summary OR and 95 % confidence intervals (CIs) were used to assess the strength of association between the polymorphism and cancer risk. The genetic models evaluated for the pooled OR of the polymorphisms were homozygote comparison (GG versus AA), heterozygote comparison (AG versus AA), dominant model (GG+AG versus AA), and recessive model (GG versus AG+AA). Stratified analyses were also performed by ethnicity and source of controls. The heterogeneity between the studies was estimated using the chisquare-based Q test. If the P value of the Q test was
RESEARCH ARTICLE
Regulator of telomere elongation helicase 1 (RTEL1) rs6010620 polymorphism contribute to increased risk of glioma Wei Zhao & Yusong Bian & Wei Zhu & Peng Zou & Guotai Tang
Received: 30 December 2013 / Accepted: 22 January 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Regulator of telomere elongation helicase 1 (RTEL1) is critical for genome stability and tumor avoidance. Many studies have reported the associations of RTEL1 rs6010620 with glioma risk, but individually published results were inconclusive. This meta-analysis was performed to quantitatively summarize the evidence for such a relationship. The PubMed, Embase, and Web of Science were systematically searched to identify relevant studies. The odds ratio (OR) and 95 % confidence interval (95 % CI) were computed to estimate the strength of the association using a fixed or random effects model. Ten studies were eligible for meta-analysis including data on glioma with 6,490 cases and 9,288 controls. Overall, there was a significant association between RTEL1 rs6010620 polymorphism and glioma risk in all four genetic models (GG vs. AA: OR = 1.87, 95 % CI = 1.60–2.18, Pheterogeneity =0.552; GA vs. AA: OR=1.30, 95 % CI=1.16– 1.46, Pheterogeneity =0.495; dominant model—GG+GA vs. AA: OR=1.46, 95 % CI=1.31–1.63, Pheterogeneity =0.528; recessive model—GG vs. GA+AA: OR=1.36, 95 % CI=1.27– 1.46, Pheterogeneity =0.093). Subgroup analyses by ethnicity showed that RTEL1 rs6010620 polymorphism resulted in a higher risk of glioma among both Asians and Caucasians. In the stratified analysis by ethnicity and source of controls, significantly increased risk was observed for Asians and Europeans in all genetic models, population-based studies in all genetic models, and hospital-based studies in three genetic models (heterozygote comparison, homozygote comparison, and dominant model). Our meta-analysis suggested that
Wei Zhao and Yusong Bian contributed equally to this study, and they should be regarded as joint first authors. W. Zhao : Y. Bian : W. Zhu : P. Zou (*) : G. Tang (*) Department of Neurosurgery, Yuhuangding Hospital of Yantai, 20 Yuhuangding East Road, Yantai 264000, Shandong, China e-mail: [email protected] e-mail: [email protected]
RTEL1 rs6010620 polymorphism is likely to be associated with increased glioma risk, which lends further biological plausibility to these findings. Keywords Cancer . Meta-analysis . Polymorphism . RTEL1 Abbreviations RTEL1 Regulator of telomere elongation helicase 1 OR Odds ratio CI Confidence interval HWE Hardy–Weinberg equilibrium PB Population-based HB Hospital-based
Introduction Gliomas that originate from glial cells surrounding and supporting neurons are the most common primary tumors of the central nervous system (CNS), accounting for the vast majority (80 %) of malignant primary brain tumors (PBT) [1–4]. Although the etiology of glioma remains unclear, exposure to moderate- to high-doses of ionizing radiation may be the only contributing factor identified currently [1, 5–7]. However, this only explains a small proportion of cases, suggesting that other causes, including genetic susceptibility, might play a pivotal role in modifying glioma occurrence. DNA repair and telomere maintenance are essential for genomic stability. Regulator of telomere elongation helicase 1 (RTEL1), a DNA helicase crucial for regulation of telomere length, has been shown to contribute to genome maintenance, both at telomeres and at sites of mitotic DNA damage as well as promoting meiotic synthesis-dependent strand annealing [8–11]. In the absence of RTEL1, shortened telomere length, chromosome breaks, and translocations were observed,
Tumor Biol.
demonstrating the possibility that RTEL1 protein may function to protect the genome against instability [8, 12, 13]. Furthermore, RTEL1-depleted mice died between days 10 and 11.5 of gestation, having severe defects that involve multiple organs including the nervous system, vasculature, heart, and extraembryonic tissues [8]. Upregulation of RTEL1 may be a critical event that accelerates the onset of liver carcinogenesis, gastrointestinal tract tumors, and breast cancers in mammals [14–18]. It has been demonstrated that human RTEL1 genomic locus (20q13.3) was amplified in approximately 30 % of gliomas with copy number change correlating with RTEL1 expression [19]. Together, inappropriate RTEL1 expression cells will undergo uncontrolled homologous recombination and result in telomere loss or gain and chromosomal translocations and rearrangements, all of which could drive genome instability and tumorigenesis. Single nucleotide polymorphisms (SNPs), the most common type of sequence variations in the human genome, contribute to human phenotypic differences [20]. RTEL1 gene locates in chromosome 20q13.3 with the length of 40.889 kb, including 40 exons. Rs6010620 maps to intron 12 of the RTEL1 and locates within a 65-kb region of linkage disequilibrium at 20q13.33 [12]. Recently, a number of studies have reported the role of this SNP and glioma risk, but the results are inconclusive [19, 21–24]. Meta-analysis is a powerful concept and tool which is directed toward the quantitative integration of findings from various studies. In the present study, we carried out a meta-analysis including subgroup analysis on all eligible case-control studies to derive a more precise estimation of the association between RTEL1 rs6010620 polymorphism and glioma risk. Heterogeneity, publication bias, and sensitivity analysis were also explored.
Materials and methods Publication search We searched electronic databases PubMed, Embase, and Web of Science (last search was updated on 10 Oct 2013). The following search terms were used in isolation and combination with one another: “RTEL1 OR rs6010620” AND “polymorphism OR variant or mutation” AND “glioma” using the limits, Humans, English, Cancer. The related reference articles of original studies on this topic were checked for other relevant articles. All studies matching the eligible criteria were included in our meta-analysis. Inclusion criteria Eligible studies included in our meta-analysis have to meet all the following criteria: (a) evaluation of the association
between RTEL1 rs6010620 polymorphism and glioma risk, (b) use a case-control design, and (c) sufficient data for estimating odds ratios (ORs) with their 95 % confidence interval (CI). Articles that were not about cancer research, contained duplicated previous research, or did not include usable genotype data were excluded. Data extraction Two investigators independently extracted the necessary data from all eligible publications and reached a consensus on all items. For each study, the following information was collected: the name of first author, year of publication, country origin, ethnicity (European or Asian), cancer type, source of controls (population- or hospital-based controls or mixed (composed of both population- and hospital-based controls)), total number of cases and controls, numbers of cases and controls with RTEL1 rs6010620 polymorphism genotypes, G allele frequency in controls, and P value for Hardy– Weinberg equilibrium. Statistical methods The departure from the Hardy–Weinberg equilibrium for the control group in each study was assessed with Pearson’s goodness-of-fit chi-square test with 1 degree of freedom. The summary OR and 95 % confidence intervals (CIs) were used to assess the strength of association between the polymorphism and cancer risk. The genetic models evaluated for the pooled OR of the polymorphisms were homozygote comparison (GG versus AA), heterozygote comparison (AG versus AA), dominant model (GG+AG versus AA), and recessive model (GG versus AG+AA). Stratified analyses were also performed by ethnicity and source of controls. The heterogeneity between the studies was estimated using the chisquare-based Q test. If the P value of the Q test was
