Original Article PLCE1 Rs2274223 Polymorphism and Risk of Gastric Cancer: a Meta-Analysis Based on 14 Publications

Int J Clin Exp Med 2016;9(2):1540-1548 www.ijcem.com /ISSN:1940-5901/IJCEM0009768

Original Article PLCE1 rs2274223 polymorphism and risk of gastric cancer: a meta-analysis based on 14 publications

Gang Chen1, Jianying Shangguan2, Jianjun Ye1, Xiangyong Yan3, Xianghui Wang2, Ruifang Fan2, Hongjun Xiang2

Departments of 1Image, 2Hepatobiliary Surgery, 3traditional Chinese Medicine, Lanzhou General Hospital, Lan- zhou Command of Chinese PLA, Lanzhou 730050, China Received April 30, 2015; Accepted September 28, 2015; Epub February 15, 2016; Published February 29, 2016

Abstract: Background: PLCE1 rs2274223 polymorphism is reportedly associated with gastric cancer. However, fo- cusing on various populations or other different elements, these published articles provided diverging results, so a meta-analysis was needed under such a circumstance. Methods: Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were employed to assess the association betweenPLCE1 rs2274223 polymorphism and gastric cancer susceptibility. Heterogeneity among included publications was examined with chi-square-based Q test, with significance whenP <0.1. Sensitivity analysis was performed through omitting one single study one time to detect any one with substantial influence on the whole results. Publication bias was measured with Begg’s funnel plot and Egger’s test. Results: PLCE1 rs2274223 polymorphism expressed a significant association with increased risk of gastric cancer under all five models (GG versus AA: OR = 1.29, 95% CI = 1.02-1.64; GG + AG versus AA: OR = 1.10, 95% CI = 1.01-1.20; GG versus AA + AG: OR = 1.24, 95% CI = 1.01-1.52; G versus A: OR = 1.16, 95% CI = 1.07- 1.25; AG versus AA: OR = 1.09, 95% CI = 1.01-1.19). The positive relationship was also found in Asian subgroup under five contrasts except AG versus AA model, in population-based subgroup under GG + AG versus AA, G versus A and AG versus AA models, in non-cardia gastric cancer subgroup under G versus A model as well as in cardia gastric cancer subgroup under G versus A and AG versus AA models. Conclusion: Genetic variant rs2274223 may increase the susceptibility to gastric cancer, which should be further demonstrated in studies considering other risk factors.

Keywords: PLCE1, gastric cancer, polymorphism

Introduction PLCE1 can hydrolyze phosphatidylinositol- 4,5-bisphosphate to generate the second mes- Gastric cancer (GC), one of the most common sengers inositol 1,4,5-triphosphate and diacyl- tumors worldwide, originates from gastric epi- glycerol, and participate in cellular signal thelium, accounting for 95% of gastric malig- transduction, thus regulating cell growth and nancies and ranking the third place among differentiation [9-11]. Non-synonymous poly- malignant tumors [1-3]. The incidence rate and morphism rs2274223 in PLCE1 gene which mortality of gastric cancer also lead among encodes PLCE1 protein has been certified to be cancers around the world, gravely jeopardizing a facilitator for histidine transforming to argi- human health [4, 5]. In early stage, gastric can- nine [12, 13]. This polymorphism has been cer shows no symptoms or only presents some widely studied its relationship with digestive slight signs similar to dyspepsia, thus leading to delayed diagnosis and treatment [6]. In China, system cancers, including gastric cancer [14, due to low diagnostic and survival rate as well 15]. as poor prognosis, the morbidity and mortality of gastric cancer are more higher than other Though having achieved great research prog- countries [7]. So it is an urgent task to ascer- ress, the studies on PLCE1 rs2274223 poly- tain more knowledge about the exact patho- morphism and gastric cancer susceptibility in genesis of gastric cancer. different populations got inconsistent results, making a meta-analysis necessary to statisti- Phospholipase C epsilon 1 (PLCE1) is a newly cally summarize their outcomes for a relatively found isozyme in phospholipase family [8]. decisive conclusion. PLCE1 rs2274223 polymorphism and gastric cancer

genotyping method and the number of cases and controls.

Statistical analysis

The association of PLCE1 rs2274223 polymorphism with gastric cancer susceptibility was evaluated with odds ratios (ORs) and their 95% confidence intervals (95% CIs) under five comparison models. Stratified analyses were carried out based on ethnicity, source of control and type of gastric cancer, respective- Figure 1. Flow diagram for literature selection. ly. A chi-square-based Q sta- tistic was employed to exam- ine the heterogeneity across Materials and methods the selected articles, and its result represented significant heterogeneity whenP value was less Literature search strategy than 0.1, which meant the use of random- effects model for OR calculation; whereas The electronic databases of PubMed, Elsevier fixed-effects model would be chosen if P value Science Direct and CNKI were searched for was not less than 0.1. Any study with substan- potentially relevant publications. Search strat- tial influence on the whole result was detected egy adopted the following terms: (1) represent- in sensitivity analysis through sequential dele- ing gastric cancer (e.g. “gastric cancer” or tion to observe the change in results. Begg’s “stomach carcinoma”); (2) standing for PLCE1 funnel plot visually revealed whether publica- (e.g. “PLCE1” or “phospholipase C epsilon 1”); tion bias among studies was significant, while and (3) referring to polymorphism (e.g. “poly- Egger’s linear regression test provided statisti- morphism” or “genetic variant”). The referenc- cal evidence (P<0.05 meant the presence of es of relevant articles were manually searched significance) [16, 17]. for additional publications. Results Inclusion and exclusion criteria Study characteristics The criteria for included papers were as follows: (1) with case-control study design; (2) evaluat- Through the above search strategy, a total of ing the association between PLCE1 polymor- 140 articles were identified from the databas- phisms and gastric cancer susceptibility; (3) es of PubMed (37), Elsevier Science Direct (82) samples containing healthy controls and patho- and CNKI (21). Among them, 85 papers were logically or histologically confirmed gastric can- excluded for reviews (6), about basic science cer patients; and (4) using validated genotyping (11), duplicate publications (5) and irrelevant methods. Case reports, review articles and studies (63). 41 publications were ultimately papers without available data were excluded. excluded from the above 55 ones after reading texts, so finally 14 articles were included in the Data extraction meta-analysis [18-31]. Figure 1 displays the selection process in detail. The principal infor- Two authors took charge of data extraction sep- mation in selected articles is listed in Table 1, arately according to the same principle. Any dis- which includes 19 case-control studies. crepancy in this process was solved through discussion among all authors. For all included Meta-analysis results articles, the principal information to be extract- ed contained first author, year of publication, The overall and stratification analysis results original country, ethnicity, source of control, under five comparison models are shown in

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Table 1. Main characteristics of all studies included in the meta-analysis Control Genotyping Cancer First author-Year Country Ethnicity Cases Controls HWE source method type Palmer-2012 US Caucasian PB PCR NCGC 184 210 0.039 Palmer-2012 US Caucasian PB PCR CGC 122 210 0.039 Palmer-2012 Poland Caucasian PB PCR NCGC 289 376 0.307 Malik-2014 Kashmir Valley Asian PB PCR-RFLP Unknown 108 195 0.748 Zhao-2014 China Asian PB PCR-DHPLC Unknown 120 120 0.222 Zhao-2014 China Asian PB PCR-DHPLC Unknown 120 120 0.615 Kupcinskas-2014 Lithuania/Latvia Caucasian HB RT-PCR/TaqMan Unknown 250 241 0.76 Liang-2014 China Asian PB MassArray Unknown 476 481 0.999 Li-2013 China Asian HB PCR CGC/NCGC 335 334 0.184 Zhang-2011 China Asian PB TaqMan CGC 812 1848 0.451 Zhang-2011 China Asian PB TaqMan NCGC 720 1848 0.451 Wang-2012 China Asian PB PCR CGC/NCGC 1059 1240 0.224 Song-2013 Korea Asian HB PCR CGC/NCGC 3245 1700 0.148 Yang-2012 China Asian HB MassArray Unknown 249 292 / Wang-2010 China Asian HB PCR CGC 2766 11013 / Abnet-2010 China Asian PB Illumina/TaqMan CGC 1213 3302 / Abnet-2010 China Asian PB Illumina/TaqMan NCGC 917 3302 / Shi-2011 China Asian HB Affymetrix NCGC 1006 2273 / Jia-2011 China Asian HB Illumina CGC 516 995 / CGC: Cardia gastric cancer; NCGC: Non-cardia gastric cancer; PCR: Polymerase chain reaction; PCR-RFLP: PCR-restriction frag- ment length polymorphism; Taq Man: TaqManSNP; HWE: Hardy-Weinberg equilibrium.

Table 2. PLCE1 rs2274223 polymorphism, = 1.31-1.44) and AG versus AA (OR = 1.28, 95% overall, had a significant association with CI = 1.11-1.48) models (Figures 3, 4). increased risk of gastric cancer under GG versus AA (OR = 1.29, 95% CI = 1.02-1.64), GG + Sensitivity analysis AG versus AA (OR = 1.10, 95% CI = 1.01-1.20), GG versus AA + AG (OR = 1.24, 95% CI = 1.01- Results showed no significant variation after 1.52), G versus A (OR = 1.16, 95% CI = 1.07- omitting one single study every time in the 1.25) and AG versus AA (OR = 1.09, 95% CI = whole process of sensitivity analysis, implying 1.01-1.19). Furthermore, similar results were the stability of the outcomes. obtained in subgroup analyses by ethnicity, Publication bias source of control and type of gastric cancer. In Asian group, the results under four contrasts Symmetric shapes of funnel plots for all com- with significance were as follows: GG versus AA parison models showed no significant publica- (OR = 1.46, 95% CI = 1.08-1.99), GG + AG ver- tion bias, which was further proven by statisti- sus AA (OR = 1.13, 95% CI = 1.02-1.27), GG cal evidence from Egger’s test (P = 0.141) versus AA + AG (OR = 1.38, 95% CI = 1.06-1.79) (Figure 5). and G versus A (OR = 1.20, 95% CI = 1.10-1.30) (Figure 2). The polymorphism expressed a posi- Discussion tive relationship with gastric cancer susceptibility in population-based group under GG + AG PLCE1 is a recently discovered isozyme of versus AA (OR = 1.17, 95% CI = 1.09-1.25), G phospholipase C. According to bioinformatics versus A (OR = 1.16, 95% CI = 1.06-1.28) and analysis, PLCE1 possesses a domain combin- AG versus AA (OR = 1.16, 95% CI = 1.07-1.25) ing with DNA-PKcs, and may be involved in the models, in non-cardia gastric cancer group regulation of RAS-BRAF signal pathway closely under G versus A (OR = 1.10, 95% CI = 1.03- related to the pathogenesis of gastric cancer 1.17) contrast as well as in cardia gastric can- [32, 33]. PLCE1 gene, located on chromosome cer group under G versus A (OR = 1.37, 95% CI 10q23.32, contains 34 exons with a total

1542 Int J Clin Exp Med 2016;9(2):1540-1548 PLCE1 rs2274223 polymorphism and gastric cancer

Table 2. PLCE1 rs2274223 polymorphism and gastric cancer risk GG versus AA GG + GA versus AA GG versus AA + GA G versus A GA versus AA

OR (95% CI) Ph OR (95% CI) Ph OR (95% CI) Ph OR (95% CI) Ph OR (95% CI) Ph Random-effects model Ethnicity Caucasian 0.99 (0.73, 1.32) 0.942 1.01 (0.87, 1.17) 0.954 0.95 (0.72, 1.26) 0.956 1.00 (0.88, 1.13) 0.930 1.02 (0.86, 1.20) 0.939 Asian 1.46 (1.08, 1.99) 0.001 1.13 (1.02, 1.27) 0.011 1.38 (1.06, 1.79) 0.017 1.20 (1.10, 1.30) 0.000 1.12 (1.00, 1.25) 0.024 Source of control Population 1.34 (1.00, 1.80) 0.008 1.16 (1.07, 1.25) 0.343 1.27 (0.98, 1.65) 0.027 1.16 (1.06, 1.28) 0.001 1.16 (1.07, 1.25) 0.579 Hospital 1.10 (0.80, 1.52) 0.249 0.97 (0.89, 1.07) 0.370 1.12 (0.82, 1.52) 0.248 1.15 (1.00, 1.33) 0.000 0.96 (0.87, 1.06) 0.391 Cancer type NCGC 1.15 (0.87, 1.51) 0.783 1.04 (0.92, 1.18) 0.851 1.12 (0.86, 1.46) 0.773 1.10 (1.03, 1.18) 0.445 1.04 (0.91, 1.19) 0.838 CGC 1.67 (0.58, 4.83) 0.020 1.21 (0.87, 1.68) 0.085 1.58 (0.64, 3.86) 0.042 1.37 (1.28, 1.46) 0.179 1.20 (0.90, 1.62) 0.138 Other 1.16 (0.97, 1.39) 0.406 1.07 (0.98, 1.18) 0.253 1.14 (0.96, 1.35) 0.491 1.08 (0.99, 1.18) 0.163 1.07 (0.97, 1.19) 0.219 Total 1.29 (1.02, 1.64) 0.003 1.10 (1.01, 1.20) 0.047 1.24 (1.01, 1.52) 0.021 1.16 (1.07, 1.25) 0.000 1.09 (1.01, 1.19) 0.099 Fixed-effects model Ethnicity Caucasian 0.98 (0.73, 1.32) 0.942 1.01 (0.87, 1.17) 0.954 0.95 (0.72, 1.26) 0.956 1.00 (0.88, 1.13) 0.930 1.02 (0.86, 1.20) 0.939 Asian 1.40 (1.21, 1.62) 0.001 1.10 (1.04, 1.17) 0.011 1.36 (1.18, 1.57) 0.017 1.22 (1.18, 1.27) 0.000 1.09 (1.02, 1.16) 0.024 Source of control Population 1.47 (1.25, 1.73) 0.008 1.17 (1.09, 1.25) 0.343 1.36 (1.16, 1.60) 0.027 1.21 (1.15, 1.27) 0.001 1.16 (1.07, 1.25) 0.579 Hospital 1.08 (0.88, 1.34) 0.249 0.97 (0.89, 1.07) 0.370 1.12 (0.91, 1.37) 0.248 1.21 (1.16, 1.26) 0.000 0.96 (0.87, 1.06) 0.391 Cancer type NCGC 1.15 (0.87, 1.51) 0.783 1.04 (0.92, 1.18) 0.851 1.11 (0.85, 1.45) 0.773 1.10 (1.03, 1.17) 0.445 1.04 (0.91, 1.19) 0.838 CGC 2.30 (1.70, 3.10) 0.020 1.31 (1.15, 1.50) 0.085 2.03 (1.52, 2.72) 0.042 1.37 (1.31, 1.44) 0.179 1.28 (1.11, 1.48) 0.138 Other 1.16 (0.98, 1.38) 0.406 1.05 (0.98, 1.13) 0.253 1.14 (0.97, 1.35) 0.491 1.06 (0.99, 1.12) 0.163 1.04 (0.96, 1.13) 0.219 Total 1.31 (1.15, 1.49) 0.003 1.09 (1.03, 1.15) 0.047 1.26 (1.11, 1.43) 0.021 1.21 (1.17, 1.25) 0.000 1.08 (1.02, 1.15) 0.099

CGC: Cardia gastric cancer; NCGC: Non-cardia gastric cancer; Other: Unclassified information; AA: Wide-type homozygote; AG: Heterozygote; GG: Rare homozygote; Ph: P-value of heterogeneity test.

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Figure 2. Forest plot for the association of PLCE1 rs2274223 polymorphism with gastric cancer susceptibility in stratified analysis by ethnicity under G versus A model. length of 334.3 kb, and further exploration has To further eliminate some disturbing factors, revealed that genetic polymorphisms in this we also performed stratification analyses by gene may affect the phosphorylation and meth- ethnicity, source of control and type of gastric ylation of PLCE1 protein, consequently impact- cancer. As a result, the positive association ing the biological functions of PLCE1 [34]. Three between the polymorphism and gastric cancer genome-wide association studies in China and risk was observed in Asian group under five Japan found a significant correlation of PLCE1 contrasts except AG versus AA; the similar gene polymorphisms with the susceptibility to results were obtained in population-based gastric cancer and esophageal carcinoma, indi- group under GG + AG versus AA, G versus A and cating PLCE1 polymorphisms may be potential AG versus AA models, in non-cardia gastric can- molecular markers for early warning or diagno- cer group under G versus A contrast as well as sis of gastric cancer [18, 19, 35]. in cardia gastric cancer group under G versus A and AG versus AA models. Whereas no signifi- Based on published studies on the association cant relationship of the polymorphism with gas- of PLCE1 polymorphisms and gastric cancer, tric cancer was found in Caucasian or hospital- the results from our meta-analysis showed that based or other gastric cancer type group. rs2274223 polymorphism in PLCE1 gene was significantly correlated with increased risk of As for significant heterogeneity under all five gastric cancer under five comparison models. contrasts, they were all removed in Caucasian,

1544 Int J Clin Exp Med 2016;9(2):1540-1548 PLCE1 rs2274223 polymorphism and gastric cancer

Figure 3. Forest plot for the association of PLCE1 rs2274223 polymorphism with gastric cancer susceptibility in stratified analysis by source of control under G versus A model. non-cardia gastric cancer and other gastric ple factors, so merely one SNP is not enough cancer type groups, and were partially alleviat- for us to totally understand the precise etiology, ed or even eliminated in hospital-based and which means lots of work needs to be done, cardia gastric cancer groups. This phenomenon including the exploration of interactions among implied that inter-study heterogeneity might be risk elements for gastric cancer [36, 37]. And associated with ethnicity, source of control and this may account for the discrepancy among type of gastric cancer. In the meta-analysis, results from studies on different populations in funnel plots for all models were symmetric, and various conditions. Apart from the lack of inter- Egger’s test gave statistical evidence to certify action analysis, the present meta-analysis inev- the absence of significant publication bias itably had some other restrictions. Language across the selected articles. No dramatic restriction, for example, might lead to the loss change occurred in sensitivity analysis, show- of some important articles published in other ing the stability of the results. All these exami- languages. Meanwhile, we searched only a few nation outcomes indicated our results were electronic databases, and potentially relevant statistically robust. papers from other sources might be missed.

Gastric cancer, just like other cancers, has a To sum up, the result in the analysis manifested complex pathogenesis connecting with multi- that PLCE1 rs2274223 polymorphism might

1545 Int J Clin Exp Med 2016;9(2):1540-1548 PLCE1 rs2274223 polymorphism and gastric cancer

Figure 4. Forest plot for the association of PLCE1 rs2274223 polymorphism with gastric cancer susceptibility in stratified analysis by cancer type under G versus A model.

Figure 5. Begg’s funnel plot for publication bias across included studies under G versus A model.

increase the risk of gastric cancer. The conclusion, however, needs to be verified in future due to restrictions. To obtain a clearer understand- ing of PLCE1 rs2274223 polymorphism and etiology of gastric cancer, later studies should incorporate more samples and interaction analyses of risk factors in various populations.

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