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Common SEP15 Polymorphisms and Susceptibility to Cancer: a Systematic Review and Meta-Analysis

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893 Original Article Common SEP15 polymorphisms and susceptibility to cancer: a systematic review and meta-analysis Qiao-Chao Chen1, Xiang-Li Ding2, Shao-Fang Zhu3, Lei Su1, Dong-Mei Cai3, Long Chen1, Wen He1 1Department of Geriatrics, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; 2Department of Urology, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China;3 Department of Internal Medicine, First Affiliated Hospital of Sun Yat- sen University, Guangzhou 510080, China Contributions: (I) Conception and design: QC Chen, XL Ding; (II) Administrative support: W He; (III) Provision of study materials or patients: SF Zhu, QC Chen, XL Ding; (IV) Collection and assembly of data: TF Zhu; (V) Data analysis and interpretation: QC Chen, XL Ding; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Wen He. Department of Geriatrics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou 510080, China. Email: [email protected]. Background: Some studies have shown that genetic polymorphisms in the 15 kDa selenoprotein (SEP15) gene can alter the interaction of Sep15 protein with selenium (Se), which is associated with increased susceptibility to cancer. However, the results of other studies are conflicting and ambiguous. Methods: To evaluate the associations between two common SEP15 polymorphisms (rs5859 and rs5845) and susceptibility to cancer, we conducted a comprehensive literature research of several electronic database, including PubMed, EMBASE, Cochrane Library, and Web of Science. We enrolled all relevantly eligible studies that were published by December 17, 2016. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. Results: A total of nine publications comprising 10 case-control studies were enrolled for two SEP15 polymorphisms (rs5859 and rs5845). For the rs5859 polymorphism, we enrolled 5,802 cases and 7,035 controls from seven case-control studies, whereas for the rs5845 polymorphism, three case-control studies comprising 1,168 cases and 1,397 controls were included. Overall, the results demonstrated that neither the rs5859 nor rs5845 polymorphism was related to cancer susceptibility. In addition, stratification analyses based on ethnicity, cancer type, Hardy Weinberg equilibrium (HWE) status, and source of control generated null results. Conclusions: The results of this study show that SEP15 polymorphisms (rs5859 and rs5845) are not risk factors for cancer. Future well-designed studies with larger sample sizes are needed to validate these findings. Keywords: 15 kDa selenoprotein polymorphisms (SEP15 polymorphisms); selenium (Se); cancer susceptibility; meta-analysis Submitted May 02, 2017. Accepted for publication Jul 24, 2017. doi: 10.21037/tcr.2017.08.16 View this article at: http://dx.doi.org/10.21037/tcr.2017.08.16 Introduction understood. An increasing number of studies have reported that cancer is a complex disease influenced by various Cancer is a global health problem that results in significant environmental and genetic factors and their interactions morbidity and mortality (1). Recent estimates indicate that (3,4). In addition, several genes have been associated with approximately 4,292,000 new cancer cases and 2,814,000 cancer susceptibility (5) cancer deaths are reported in China each year (2). To Selenoproteins are a class of proteins characterized date, the exact mechanisms of carcinogenesis are poorly by incorporation of selenium (Se) in the form of the © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2017;6(5):886-893 Translational Cancer Research, Vol 6, No 5 October 2017 887 amino acid (6). Studies investigating the association of frequencies. Meanwhile, the exclusion criteria were as Se with cancer susceptibility have described the role of follows: duplicate data; clinical cases, comments, series, Secis carcinogenesis. The 15 kDa selenoprotein (SEP15) and reviews; and insufficient data. Studies published in and other members of the thioredoxin family (7) are a languages other than English were also excluded. Articles type of catalyzing agent that can regulate the cellular with two or more case-control cohorts were regarded as two redox reaction and reduce cumulative oxidative stress, or more different studies. which has correlates with cell death and oncogenesis (8). A recent study has shown that SEP15 is unregulated in Data extraction the prostate gland (9) and binds to uridine diphosphate (UDP)-glucose:glycoprotein glucosyltransferase (10-12), a Two investigators independently reviewed the reports that regulatory protein of N-linked glycoprotein folding in the fulfilled the selection criteria and extracted the following endoplasmic reticulum, which suggests that SEP15 plays an data: name of first author; year of publication; country essential function in this particular pathway. of origin; ethnicity; and source of controls (population- Recent studies have described the association between based or hospital-based controls). The Newcastle-Ottawa SEP15 polymorphisms and the risk of various cancers, scale (NOS) was applied to assess the quality of the studies including colorectal cancer (CRC) (13,14), lung cancer included in our analysis. Different ethnic groups, including (LC) (15), breast cancer (BC) (16-18), and prostate cancer Caucasians, Asians, and Africans, were analyzed to assess the (PCa) (19-21). However, the results of these studies are effects of SEP15 polymorphisms on cancer susceptibility. conflicting and inconclusive, possibly due to clinical heterogeneity, different ethnic populations, and small Statistical analysis sample sizes. To circumvent these limitations, we conducted a meta-analysis of the results of relevant studies to evaluate The strength of the association between SEP15 polymorphisms the association between SEP15 polymorphisms and cancer and tumor susceptibility was assessed by the odds ratios susceptibility. (ORs) with 95% confidence intervals (CIs). For SEP15 polymorphisms, the susceptibility of dominant (MM + MW vs. WW), recessive (MM vs. MW + WW), co-dominant Methods (MW vs. WW; MM vs. WW), and allele models (M vs. W) Publication search eligibility of relevant studies was evaluated, respectively (M: mutant allele; W: wild-type allele). Subgroup analyses were also conducted by ethnicity, All case-control studies included in this study were queried source of control, and cancer type. The Hardy Weinberg from PubMed, EMBASE, Cochrane Library, and Web of equilibrium (HWE) was used to assess the genotype Science using the following keywords: “SEP15 OR 15kDa frequencies of SEP15 polymorphisms among the controls selenoprotein” AND “variant OR mutation OR SNP OR using the χ2 test. Meta-analysis was performed by the polymorphism” AND “cancer OR tumor OR carcinoma Mantel-Haenszel method in accordance with the Cochrane OR malignancy OR neoplasms”. Only relevant studies in organization guidelines. The heterogeneity between humans were included, and the language was restricted to datasets was evaluated by the heterogeneity index (I2) and English. In addition, references of eligible publications were the Cochran’s Q statistic (22). P-het <0.10 was considered searched manually. When certain data were not mentioned as significant heterogeneity. The Fixed-effects model was in the report, the corresponding author of the publication applied when I2 was <50%, while random-effects model was was contacted by e-mail. The most recent or complete used when I2 was >50% (23). Funnel plots were applied to articles with the largest number of subjects were selected test for publication bias (24). The forest plot was generated from overlapping data of reports by the same authors. The using the Review Manager software (RevMan, version 5.3; last search was performed on December 17, 2016. Copenhagen: The Nordic Cochrane Centre, The Cochrane Eligible studies included in the meta-analysis met Collaboration, 2014). All analyses were performed with the following inclusion criteria: assessed the association Stata software ver. 12.0. between SEP15 polymorphisms (rs5859 and rs5845) and Power analysis for association of SEP15 polymorphisms susceptibility to cancer; were case-control studies designed and tumor susceptibility was performed using the Genetic for human subjects; and provided useful data on genotype Power Calculator (13). © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2017;6(5):886-893 © Translational CancerResearch. Allrightsreserved. © Translational 888 Table 1 Characteristics of the eligible studies included in the meta-analysis Source of Cancer Cases Controls Polymorphism Reference Year Ethnicity control type WW MW MM WW MW WW HWE rs5859 Penney et al. 2010 Caucasian H-B PCa 751 (63%) 387 (32%) 57 (5%) 738 (62%) 394 (33%) 54 (5%) Y Steinbrecher et al. 2010 Caucasian P-B PCa 165 (67%) 78 (31%) 5 (2%) 309 (63%) 157 (31%) 26 (5%) Y Meplan et al. 2010 Caucasian H-B CRC 682 (51%) 423 (32%) 229 (17%) 626 (51%) 388 (32%) 214 (17%) N Jablonska et al. 2015 Caucasian H-B BC 82 (57%) 8 (6%) 54 (37%) 103 (60%) 14 (8%) 80 (47%) N Jablonska et al. 2008 Caucasian H-B LC 189 (58%) 117 (36%) 19 (6%) 161 (50%) 108 (33%) 18 (6%) Y Sutherland et al. 2010 Asian H-B CRC 790 (96%) 34 (4%) 3 (0.3%) 705 (96%) 25 (3%) 3 (0.4%) N Pellatt et al. 2013 Caucasian H-B BC 1,093 (63%) 554 (32%) 82 (5%) 1,878 (64%) 925 (32%) 109 (4%) Y rs5845 Karunasinghe et al. 2012 Caucasian H-B PCa 160 (62%) 84 (33%) 14 (5%) 337 (60%) 197 (35%) 31 (5%) Y Sutherland et al. 2010 Asian H-B CRC 793 (96%) 34 (4%) 0 (0%) 707 (97%) 25 (3.4%) 1 (0.1%) Y Watrowski et al. 2015 Caucasian H-B BC 53 (64%) 28 (34%) 2 (2%) 69 (70%) 28 (28%) 2 (2%) Y W, wild-type allele; M, mutant allele; PCa, prostate cancer; CRC, colorectal cancer; BC, bladder cancer; LC, lung cancer; HWE, Hardy-Weinberg Equilibrium; H-B, hospital- based; P-B, population-based; Y, study conformed to HWE; N, study did not conform to HWE. tcr.amegroups.com seven studies comprising a total of 5,802 cases and 7,035 seven studiescomprisingatotalof5,802casesand7,035 the For 2016.
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