Meta-Analysis
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2017; 23(12): 2234-2245
Published online Mar 28, 2017. doi: 10.3748/wjg.v23.i12.2234
Association between COX-2 -1195G>A polymorphism and gastrointestinal cancer risk: A meta-analysis
Xiao-Wei Zhang, Jun Li, Yu-Xing Jiang, Yu-Xiang Chen
Xiao-Wei Zhang, Jun Li, Yu-Xiang Chen, Department of Gastrointestinal and Vascular Surgery, Deyang People’s Hospital, Deyang 618099, Sichuan Province, China
Yu-Xing Jiang, Department of General Surgery and Center for Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
Author contributions: Zhang XW and Chen YX conceived and designed the study; Li J and Jiang YX designed the data extraction tool and conducted the literature search; Zhang XW and Li J interpreted and extracted the data; Zhang XW, Li J and Jiang YX performed the statistical analysis; Zhang XW and Li J wrote the first draft of the manuscript; Jiang YX and Chen YX contributed to the revision of the manuscript.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yu-Xiang Chen, Chief Physician, Department of Gastrointestinal and Vascular Surgery, Deyang People’s Hospital, Deyang 618099, Sichuan Province, China. 773854798@qq.com
Telephone: +86-838-2418116 Fax: +86-838-2418116
Received: December 6, 2016
Peer-review started: December 8, 2016
First decision: February 9, 2017
Revised: February 26, 2017
Accepted: March 4, 2017
Article in press: March 4, 2017
Published online: March 28, 2017

Abstract
AIM

To perform a meta-analysis to investigate the association between cyclooxygenase-2 (COX-2) -1195G>A gene polymorphism and gastrointestinal cancers.

METHODS

Publications related to the COX-2 -1195G>A gene polymorphism and gastrointestinal cancers published before July 2016 were retrieved from PubMed, EMBASE, Web of Science, China Biological Medicine Database, China National Knowledge Infrastructure, and CQVIP Database. Meta-analysis was performed using Stata11.0 software. The strength of the association was evaluated by calculating the combined odds ratios (ORs) and the corresponding 95%CIs. The retrieved publications were excluded or included one by one for sensitivity analysis. In addition, the funnel plot, Begg’s rank correlation test, and Egger’s linear regression method were applied to analyse whether the included publications had publication bias.

RESULTS

A total of 24 publications related to the COX-2 -1195G>A gene polymorphism were included, including 28 studies involving 11043 cases and 18008 controls. The meta-analysis results showed that the COX-2 -1195G>A gene polymorphism significantly correlated with an increased risk of gastrointestinal cancers, particularly gastric cancer (A vs G: OR = 1.35; AA/AG vs GG: OR = 1.54; AA vs GG/AG: OR = 1.43; AA vs GG: OR = 1.80; AG vs GG: OR = 1.35). Compared to the Caucasian population in America and Europe, the COX-2 -1195G>A gene polymorphism in the Asian population (A vs G: OR = 1.30; AA/AG vs GG: OR = 1.50; AA vs GG/AG: OR = 1.35; AA vs GG: OR = 1.71; AG vs GG: OR = 1.37) significantly increased gastrointestinal cancer risk. The sensitivity analysis (P < 0.05) and the false positive report probability (P < 0.2) confirmed the reliability of the results.

CONCLUSION

The results showed that the COX-2 -1195G>A gene polymorphism might be a potential risk factor for gastrointestinal cancers. Further validation by a large homogeneous study is warranted.

Key Words: COX-2, -1195G>A, Polymorphism, Meta-analysis, Gastrointestinal cancer

Core tip: To explore the association of the cyclooxygenase-2 (COX-2) (-1195G>A) polymorphism with gastrointestinal cancers, we conducted this retrospective study. According to this meta-analysis, we discovered that the COX-2 (-1195G>A) polymorphism may be a risk factor for gastrointestinal cancers and may increase the risk of gastrointestinal cancers in the Asian population. Furthermore, we applied a false-positive report probability to make the results more credible. Our findings indicated that focusing on the COX-2 (-1195G>A) polymorphism to prevent gastrointestinal cancers may be viable.



INTRODUCTION

Gastrointestinal cancers have high morbidity and mortality worldwide, with most cases being gastric cancer and colorectal cancer[1,2]. Because currently there is still no effective early diagnosis method, patients are often diagnosed at a middle or late stage; even after treatment, their quality of life and survival time are still significantly affected[3]. Improving the early diagnosis and treatment of gastric cancer and colorectal cancer has important significance in the prognosis of patients[4,5]. Therefore, studying pathogenic mechanisms of tumours, clarifying the molecular mechanism, discovering “key” molecular markers of tumours, and predicting cancer risk in a timely fashion are key to the prevention, diagnosis, and molecular targeted therapy of gastric cancer and colorectal cancer.

Previous studies have shown that cyclooxygenase-2 (COX-2) is a rate-limiting enzyme of prostaglandin synthesis[6] and is closely associated with the development of malignant tumours[7]. COX-2 is localized in the nuclear membrane under physiological conditions and can be expressed in the cytoplasm and nucleus of corresponding tissues after inflammatory stimulation to participate in inflammatory reactions and promote the formation of a tumour inflammatory microenvironment[8]. A larger amount of literature confirmed that a high COX-2 expression level was present in many malignant tumours, including breast cancer, lung cancer, liver cancer, and nasopharyngeal carcinoma. The high COX-2 expression level was not only an early event of the development of malignant tumours but was also directly correlated with the infiltration degree, lymph node metastasis, TNM stage, and patient prognosis[9-11]. Further studies indicated that the intracellular localizations of COX-2 in tumour cells of different tissues types were different[12]. COX-2 was highly expressed in gastric cancer and colorectal cancer cells; in addition, COX-2 was expressed in macrophages and fibroblasts in tumour tissues[13]. These results indicated that COX-2 expression gradually increases during the process of malignant transformation of precancerous lesions into malignant tumours, suggesting that COX-2 is involved in the developmental process of gastric cancer and colorectal cancer; however, the specific mechanism is still not clear.

The COX-2 gene is localized at q25.2-25.3 of chromosome 1 and contains 10 exons and 9 introns with a total length of approximately 8.3 kb. COX-2 is a rapid-response gene to various factors, such as inflammatory factors, tumourigenic factors, injury, and growth factors, all of which can induce its rapid expression[14,15]. There have been already many published studies on the association between COX-2 gene polymorphisms and susceptibility to gastrointestinal cancers. It is generally considered that COX-2 -765G>C and COX-2 -8473T>C gene mutations are closely associated with the development of gastrointestinal cancers[16,17]. However, the association between COX-2 -1195G>A and gastric and colorectal cancers is still unclear. Because the COX-2 gene has larger distribution differences in populations of different ethnicities and different regions and the sample size in a single study is limited, this association cannot be entirely explained. Given the current controversial study results, we aimed to perform a meta-analysis to confirm the association between the COX-2 -1195G>A polymorphism and susceptibility to gastric and colorectal cancers.

MATERIALS AND METHODS
Retrieval strategy

We performed retrieval using the MeSH terms of (COX-2 -1195G>A or COX-2 -1195G>A) and (gastrointestinal or colorectal or colon or rectal or stomach or gastric) and (cancer or tumour or carcinoma) and (polymorphism or SNP or variant or mutation) in the following databases: PubMed, EMBASE, Web of Science, China Biological Medicine Database, China National Knowledge Infrastructure, and CQVIP Database. The relevant studies in China and other countries were retrieved. The retrieval period was between the establishment of the databases and July 2016. Relevant conference papers were manually retrieved from the journal database of the Third Military Medical University library.

Inclusion criteria

The included literature in this study met the following criteria: (1) studies about the COX-2 -1195G>A gene polymorphism and susceptibility to gastrointestinal cancers; (2) case-controlled or cohort studies; (3) gastrointestinal cancer patients as the case group; and (4) enough genotype data to calculate odds ratios (ORs) and corresponding 95% confidence internals (CIs).

Exclusion criteria

The exclusion criteria were as follows: (1) the study topic of the article was not about the COX-2 -1195G>A gene polymorphism and susceptibility to gastrointestinal cancers; (2) the studies were not case-controlled or cohort studies; (3) abstracts, reviews, case reports, or repetitively published articles; and (4) the study data were not complete or the raw data could not be obtained.

Data extraction and quality evaluation

The data were independently extracted by two researchers (Xiao-Wei Zhang, Jun Li) using the unified data table. The major extracted data included the following information: first author, publication year, country, tumour type, sources of the control group, matching criteria, genotyping method, genotype distribution in the case group and the control group, and the Hardy-Weinberg equilibrium (HWE) examination result of the control group. If the data extraction results were inconsistent, a third party was consulted to reach a consensus.

The included publications were scored using the predetermined criteria[18,19]. These criteria were extracted and modified from previous studies (Table 1). The quality evaluation scale was used to evaluate the included studies from six aspects: representativeness of cases, source of controls, case-control match, specimens used for determining genotypes, HWE, and total sample size. The scores ranged from the lowest, 0 points, to the highest, 18 points. Publications with a score < 12 were classified as “low quality” and publications with a score ≥ 12 were classified as “high quality.”

Table 1 Quality evaluation scale of the included literature.
CriterionScore
Representativeness of cases
Selected from population or cancer registry3
Selected from hospital2
Selected from pathology archives, but without description1
Not described0
Source of controls
Population-based3
Blood donors or volunteers2
Hospital-based (cancer-free patients)1
Not described0
Case-control match
Matched by age and gender3
Not matched by age and gender0
Specimens used for determining genotypes
White blood cells or normal tissues3
Tumor tissues or exfoliated cells of tissue0
Hardy-Weinberg equilibrium (HWE)
Hardy-Weinberg equilibrium in control subjects3
Hardy-Weinberg disequilibrium in control subjects0
Total sample size
> 10003
> 500 and < 10002
> 200 and < 5001
< 2000
Statistical analysis

The OR and 95%CI were used as the effective index of the study. P < 0.05 indicated that the difference was statistically significant. Five genetic models, including allele model (A vs G), dominant model (AA/AG vs GG), recessive model (AA vs GG/AG), homozygous model (AA vs GG), and heterozygous model (AG vs GG), were compared. The statistical significance of combined OR values were examined using the Z test, and the significance level was set at 0.05 (bilateral). The χ2 test was used to evaluate whether the genotypes in the control group conformed to HWE. The Cochrane Q test was performed to analyse the heterogeneity among studies[20]. P < 0.10 was considered significantly different. In addition, the I2 value was combined to quantitatively evaluate the level of heterogeneity. The I2 values were between 0% and 100%; when the value was larger, the heterogeneity was higher. When the heterogeneity examination result showed P < 0.10 or I2 > 50%, the random effects model (DerSimonian-Laird method)[21] was used to perform the analysis; otherwise, the fixed effects model (Mantel-Haenszel method)[22] was used. The included studies were deleted one by one to perform sensitivity analysis to examine the effect of a single study on the total combined effect size. Whether the included literature had publication bias was analysed through the funnel plot[23], Egger’s linear regression method[24], and Begg’s rank correlation test[25]. The meta-analysis was performed using Stata11.0 software.

The method reported by Wacholder et al[26] was used to analyse the false positive report probability (FPRP) of each significant correlation. A prior probability of 0.001 was set to detect an OR of 1.5. When the FPRP value was lower than 0.2, the correlation was noteworthy. The statistical power and FPRP value were calculated using the Excel spreadsheet provided by Wacholder et al[26].

RESULTS
Literature retrieval results

A total of 378 relevant publications were retrieved. After repetitive publications were excluded, there were 302 publications. Literature screening was performed according to the inclusion and exclusion criteria. Based on titles and abstracts, 216 publications that were irrelevant to the study topic were excluded. After abstracts and the full texts were further carefully read, 64 publications were excluded (27 publications of non-case-controlled and cohort studies, 22 publications irrelevant to gastrointestinal cancers, 14 publications of abstracts and reviews, and 1 repeatedly published article). Based on the references of the included literature, 2 more publications were obtained. A total of 24 publications were finally included, involving 11,043 cases and 18,008 controls (Figure 1).

Figure 1
Figure 1 Flow chart of literature inclusion and exclusion.
Characteristics of the included studies

Among the 24 included publications (Table 2[27-49]), 11 were reports on gastric cancer and 13 on colorectal cancer; 14 were studies in Asian populations, 8 in Caucasian populations, and 2 in mixed populations. The HWE examination results of the distribution of genotypes in the control group are shown in Table 2. Among the 24 publications, the distribution of genotypes in the control groups of 19 publications conformed to HWE. The quality score of a single study ranged from 7 to 18. There were 19 publications of high quality studies (≥ 12).

Table 2 Baseline information of the included studies.
Ref.YearCountryType of cancerSource of controlsMatching criteriaGenotypingmethodCases
Controls
HWEQuality score
AAAGGGAAAGGG
Liu et al[27]2006ChinaGastric cancerPBNADHPLC88116443757713770.62614
Siezen et al[28]2006NetherlandColorectal cancerPBAge, sex, centerPCR-RFLP1275910243128200.55817
Siezen et al[28]2006NetherlandColorectal cancerPBAge, sex, centerPCR-RFLP28313219422226410.14918
Jiang et al[29]2007ChinaGastric cancerPBAge, sexPCR-RFLP741324879163620.18716
Tan et al[30]2007ChinaColorectal cancerPBAge, sexPCR-RFLP3205021783086923000.02014
Andersen et al[31]2009DenmarkColorectal cancerPBSexTaqman23011613482258250.17715
Hoff et al[32]2009NetherlandColorectal cancerHBAge, sexPCR-RFLP21310112232124130.47114
Thompson et al[33]2009United StatesColorectal cancerPBNATaqman2751389297168150.13114
Pereira et al[34]2010PortugalColorectal cancerHBNAPCR-RFLP704341777360.63410
Zhang et al[35]2011ChinaGastric cancerPBAge, sexPCR-RFLP107184322565131750.00414
Zhang et al[36]2011ChinaGastric cancerPBAge, sexPCR-RFLP113175692415272170.02714
Jing et al[37]2012ChinaGastric cancerPBAge, sexPCR-RFLP49871951133530.05915
Li et al[38]2012ChinaGastric cancerPBNAPCR-RFLP981455373166800.46114
Shin et al[39]2012KoreaGastric cancerPBNAPCR-RFLP3254143741220.10712
Zhang et al[40]2012ChinaColorectal cancerPBNAPCR-RFLP772165062184940.0912
Andersen et al[41]2013DenmarkColorectal cancerPBNAKASP™ genotyping587313471126560610.39715
Li et al[42]2013ChinaColorectal cancerHBNAPCR-RFLP116248871793361140.0459
Makar et al[43]2013United StatesColorectal cancerPBAge, location, sexTaqman910455571198509670.16217
Makar et al[43]2013United StatesColorectal cancerPBAge, location, sexTaqman61928733958496630.90517
Makar et al[43]2013United StatesColorectal cancerPBAge, location, sexTaqman37618520509237290.82917
Makar et al[43]2013United StatesColorectal cancerPBAge, location, sexTaqman33813821558249200.20617
Ruan et al[44]2013ChinaColorectal cancerPBNAPCR-RFLP3467293953280.23212
Pereira et al[45]2014PortugalColorectal cancerHBNATaqman1438515323133160.61411
Vogel et al[46]2014NorselandColorectal cancerPBNAKBioscience110242209114110.33712
Gao et al[47]2015ChinaGastric cancerPBAge, sexTaqman861375574137570.66416
Lu et al[17]2015ChinaGastric cancerHBNAPCR-RFLP6939252735720.0007
Tao et al[48]2015ChinaGastric cancerPBAge, sexPCR-RFLP3971263165250.39715
Zamudio et al[49]2016PeruGastric cancerHBNATaqman8510332106139430.8159
Meta-analysis results

The ORs of different comparisons and the heterogeneity examination results are shown in Table 3. The results showed that COX-2 -1195G>A gene polymorphism in all of the genetic models (A vs G: OR = 1.54; AA/AG vs GG: OR = 1.24; AA vs GG/AG: OR = 1.16; AA vs GG: OR = 1.31; AG vs GG: OR = 1.18) had a significant correlation with susceptibility to gastrointestinal cancers. However, when the pre-determined prior probability was below 0.001, all of the FPRP values were higher than 0.2. This result indicated that the association was not noteworthy.

Table 3 Stratified analyses of the COX-2 -1195G>A polymorphism with risk of gastrointestinal cancers.
nAllele modelDominant modelRecessive modelHomozygous comparisonHeterozygous comparison
(A vs G)
(AA/AG vs GG)
(AA vs GG/AG)
(AA vs GG)
(AG vs GG)
OR (95%CI)PhFPRPOR (95%CI)PhFPRPOR (95%CI)PhFPRPOR (95%CI)PhFPRPOR (95% CI)PhFPRP
Total281.15 (1.04, 1.26)10.0000.731.24 (1.06, 1.45)100.8761.16 (1.04, 1.30)10.0000.9141.31 (1.08, 1.59)10.0000.8731.18 (1.04, 1.34)10.0070.915
Type of cancer
Gastric cancer111.35 (1.14, 1.59)10.0000.2661.54 (1.20, 1.96)10.0000.5191.43 (1.18, 1.72)10.0020.1741.80 (1.36, 2.39)10.0000.3181.35 (1.11, 1.65)10.0380.799
Colorectal cancer171.04 (0.94, 1.15)0.0000.9981.05 (0.87, 1.28)0.0020.9981.04 (0.93, 1.18)0.0000.9981.05 (0.83, 1.32)0.0000.9991.06 (0.90, 1.25)0.0600.998
Ethnicity
Asian141.30 (1.14, 1.48)10.0000.0691.50 (1.23, 1.84)10.0000.1671.35 (1.14, 1.60)10.0000.3761.71 (1.33, 2.18)10.0000.0931.37 (1.15, 1.62)10.0070.213
Caucasian121.00 (0.89, 1.11)0.0000.9990.91 (0.76, 1.08)0.3600.9961.01 (0.89, 1.15)0.0000.9990.91 (0.74, 1.11)0.1860.9970.92 (0.77, 1.09)0.7490.997
Mixed21.10 (0.93, 1.31)0.6120.9971.13 (0.74, 1.73)0.4660.9981.13 (0.91, 1.40)0.7810.9961.20 (0.76, 1.88)0.4820.9981.09 (0.69, 1.70)0.5340.999
Source of controls
PB221.16 (1.06, 1.25)10.0000.091.26 (1.09, 1.45)10.0030.5591.19 (1.07, 1.33)10.0000.6851.35 (1.13, 1.61)10.0000.4881.19 (1.04, 1.36)10.0310.914
HB61.12 (0.75, 1.67)0.0000.9981.14 (0.60, 2.15)0.0000.9991.08 (0.72, 1.63)0.0000.9991.15 (0.54, 2.45)0.0000.9991.12 (0.73, 1.71)0.0210.998
Study quality
High (> 9)231.15 (1.06, 1.25)10.0000.5041.25 (1.09, 1.44)10.0040.6671.19 (1.07, 1.32)10.0000.5021.34 (1.12, 1.59)10.0000.4691.19 (1.04, 1.35)10.0380.873
Low ( ≤ 9)51.13 (0.68, 1.86)0.0000.9991.17 (0.56, 2.45)0.0000.9991.09 (0.65, 1.81)0.0000.9991.17 (0.48, 2.88)0.0000.9991.16 (0.71, 1.90)0.0110.998
Genotyping method
PCR-RFLP161.23 (1.08, 1.40)10.0000.6331.46 (1.19, 1.78)10.0000.2311.24 (1.06, 1.46)10.0000.9091.58 (1.23, 2.02)10.0000.4361.35 (1.14, 1.60)10.0140.376
Taqman90.99 (0.90, 1.08)0.0490.9990.97 (0.82, 1.15)0.4280.9990.99 (0.89, 1.11)0.0630.9990.97 (0.79, 1.19)0.2680.9990.98 (0.82, 1.17)0.6690.999
Other technologies31.36 (0.86, 2.17)0.0000.9971.16 (0.58, 2.31)0.0080.9991.52 (0.84, 2.75)0.0000.9971.40 (0.55, 3.53)0.0000.9990.99 (0.62, 1.57)0.1180.999

The subgroup analysis was performed based on tumour types (Figure 2). In the gastric cancer group (A vs G: OR = 1.35; AA/AG vs GG: OR = 1.54; AA vs GG/AG: OR = 1.43; AA vs GG: OR = 1.80; AG vs GG: OR = 1.35), the results showed that the COX-2 -1195G>A gene polymorphism was significantly correlated with cancer susceptibility. Analysis of FPRP in the gastric group showed that the value in the AA vs GG/AG model (FPRP = 0.174) was lower than 0.2, indicating that the result was noteworthy. However, the COX-2 -1195G>A gene polymorphism was not significantly correlated with susceptibility to colorectal cancer.

Figure 2
Figure 2 Forest plot of the stratified analysis of the COX-2 -1195G>A dominant model (AA/AG vs GG) and susceptibility to gastrointestinal cancers in different tumour types.

When subgrouping based on ethnicity (Figure 3), in the Asian population (A vs G: OR = 1.30; AA/AG vs GG: OR = 1.50; AA vs GG/AG: OR = 1.35; AA vs GG: OR = 1.71; AG vs GG: OR = 1.37), COX-2 -1195G>A could significantly increase the risk of developing gastrointestinal cancers. In addition, in the A vs G model (FPRP = 0.069), AA/AG vs GG model (FPRP = 0.167) and AA vs GG model (FPRP = 0.093), the FPRP values were lower than 0.2, indicating that the analytic results were stable and reliable. The results did not show a significant correlation between the COX-2 -1195G>A gene polymorphism and gastrointestinal cancer susceptibility in the Caucasian and mixed populations.

Figure 3
Figure 3 Forest plot of stratified analysis of the COX-2 -1195G>A dominant model (AA/AG vs GG) and gastrointestinal cancer susceptibility in different populations.

The subgroup analysis based on the sources of the control group showed that, in the studies based on populations from communities (A vs G: OR = 1.16; AA/AG vs GG: OR = 1.26; AA vs GG/AG: OR = 1.19; AA vs GG: OR = 1.35; AG vs GG: OR = 1.19), the COX-2 -1195G>A gene polymorphism significantly correlated with gastrointestinal susceptibility. The FPRP value in the A vs G model was lower than 0.2, indicating that the correlation was noteworthy. For studies based on populations from hospitals, none of the genetic models showed a correlation with intestinal cancers.

The subgroup analysis using the quality evaluation scores showed that, in the high quality studies (A vs G: OR = 1.15; AA/AG vs GG: OR = 1.25; AA vs GG/AG: OR = 1.19; AA vs GG: OR = 1.34; AG vs GG: OR = 1.19), the COX-2 -1195G>A gene polymorphism correlated with susceptibility to the development of gastrointestinal cancers. However, the FPRP analytic values were all higher than 0.2, indicating that the analytic results were not stable. In low quality studies, the COX-2 -1195G>A gene polymorphism did not have a significant correlation with gastrointestinal cancers.

Furthermore, the subgroup analysis based on different genotyping methods showed that, in the studies using the Restriction Fragment Length Polymorphism Analysis of PCR-Amplified Fragments (PCR-RFLP) genotyping method (A vs G: OR = 1.23; AA/AG vs GG: OR = 1.46; AA vs GG/AG: OR = 1.24; AA vs GG: OR = 1.58; AG vs GG: OR = 1.35), the COX-2 -1195G>A gene polymorphism significantly correlated with gastrointestinal cancer susceptibility. However, the FPRP analysis showed that the evidence of the real correlation of positive results was not sufficient. For genotyping using Taqman and other technologies, the COX-2 -1195G>A gene polymorphism in none of the genetic models was significantly correlated with intestinal cancers.

Sensitivity analysis and cumulative analysis

The present study performed sensitivity analysis through gradual deletion of the included studies one by one. The OR value of the combined effect did not have a significant change, indicating that the analytic results were stable and reliable (Figure 4). A cumulative analysis based on the chronological order showed that the OR point estimate value and the corresponding CI trended to become stable and showed a good changing trend (Figure 5).

Figure 4
Figure 4 Analysis of the influence of a single study on the total combined OR in the dominant model (AA/AG vs GG).
Figure 5
Figure 5 Cumulative meta-analysis of the COX-2 -1195G>A polymorphism and gastrointestinal cancer susceptibility in the dominant model (AA/AG vs GG).
Publication bias

The funnel plot, Begg’s rank correlation test, and Egger’s linear correlation were used to evaluate publication bias. The funnel plots of all of the models with a correlation between the COX-2 -1195G>A gene polymorphism and gastrointestinal cancers did not have significant asymmetry. In the AA/AG vs GG model, the Begg’s rank correlation test showed P = 0.489 and the Egger’s linear correlation methods showed P = 0.690; they both suggested that there was no significant publication bias (Figure 6).

Figure 6
Figure 6 Begg’s funnel plot of the publication bias in the COX-2 -1195G>A dominant model (AA/AG vs GG).
DISCUSSION

In addition to environmental factors, the risk of cancer is also closely associated with the genetic susceptibility of an individual. Previous genetic studies indicated that gene mutations of some inducible enzymes were closely associated with various diseases, including malignant tumours and congenital malformations. These inducible enzymes change the gene expression levels and interfere with signal transduction pathways to inhibit protein synthesis and cause mRNA instability, thus achieving the purpose of changing the encoded proteins and inducing the presence of disease events. Currently, the influences of genes and genetics on the occurrence and development of gastrointestinal cancers are similar to other important factors, such as smoking, drinking, eating habits and geographical environment. Genes and genetics have gradually become the hotspots of studies on the pathogenic mechanism of gastrointestinal cancers[50,51].

COX-2 overexpression can influence the tumourigenic gene features of tumour cells, including induction of anti-apoptosis, regulation of extracellular matrix adhesion, promotion of angiogenesis, increase of metastatic potential, and influence of anti-tumour effects[52-54]. Recent studies showed that the COX-2 -1195G>A gene polymorphism generated a c-MYB binding site, thus increasing the transcription activity of the COX-2 gene. c-MYB is an active transcription factor in the haematopoietic system and gastrointestinal tract. c-MYB functions on many genes to regulate the exquisite balance between cell division, differentiation and survival[55], which further confirms that the COX-2 -1195G>A polymorphism might increase susceptibility of individuals to gastrointestinal cancers. However, there were also reports showing that this polymorphism could reduce the risk of developing gastric cancer and colorectal cancer[32]. To clarify this association, we included all case-controlled or cohort studies that met the inclusion criteria to evaluate the correlation using a meta-analysis.

Our study included 24 publications, including 11 gastric cancer publications and 13 colorectal cancer publications. A total of 11,043 cases in the case group and 18,008 cases in the control group were included. The overall meta-analysis results showed that the COX-2 -1195G>A gene in all of the genetic models (A vs G: OR = 1.54, 95%CI: 1.04-1.26, P < 0.001; AA/AG vs GG: OR = 1.24, 95%CI: 1.06-1.45, P < 0.001; AA vs GG/AG: OR = 1.16, 95%CI: 1.04-1.30, P < 0.001; AA vs GG: OR = 1.31, 95%CI: 1.08-1.59, P < 0.001; AG vs GG: OR = 1.18, 95%CI: 1.04-1.34, P = 0.007) was associated with a high risk of developing gastrointestinal cancers. The results of the publication bias and sensitivity analysis also increased the reliability of the association.

The differences in ethnicity, sources of the control population, environmental factors, and the tumour types can all change the risk of developing gastrointestinal diseases through the gene-environment interaction. Therefore, the present study performed subgroup analysis based on the different specific conditions of all of the studies. In the classification of tumour types, the results showed that the COX-2 -1195G>A gene in the AA/AG vs GG model had a clear correlation with the gastric cancer susceptibility but did not have a significant correlation with colorectal cancer, suggesting that this genotype might be a very important predisposing factor for gastric cancer. This result was also similar to the reported results in some literature. In addition, the subgroup analysis based on the ethnicity of the study population showed that the mutation frequency of this polymorphism in the Asian gastrointestinal cancer population was higher than that in the Caucasian population in America and Europe, suggesting that the presence of the COX-2 -1195G>A gene polymorphism might greatly increase susceptibility of the Asian population, as represented by Chinese and Korean populations, to gastrointestinal cancers. For the mixed population from America, there were only two reports on its association with gastrointestinal cancers. This result was not sufficient to explain the issue, and studies with a larger sample size are needed to confirm its reliability. The subgroup analysis based on the sources of the control population showed that an increase in the risk of developing gastrointestinal cancers in the population from communities had a statistical correlation with the COX-2 -1195G>A polymorphism; however, this correlation in the population from hospitals was not statistically significant. These results suggested that, in the selection of the sources of controls, the hospital population was restricted by their diseases and medications; therefore, the genotyping results might be affected. Thus, samples from the community population were more representative than those from hospitals and relevant studies should try to select those from the community population as a control group. Furthermore, we also performed subgroup analysis based on genotyping methods and found that the statistical results among subgroups had clear differences. The differences might be because the different detection methods had different theoretical bases. To make the positive rate of our analytic results more real and reliable, we performed FPRP and found that the correlation of the COX-2 -1195G>A polymorphism in the gastric cancer recessive model (FPRP = 0.174), the allele model of the Asian population (FPRP = 0.069) and the linear model (FPRP) all passed the FPRP test. These results suggested that the correlation of these two aspects had very strong reliability and the authenticity was further confirmed.

The present study had some limitations. First, during overall and subgroup analyses, we found that there was moderate heterogeneity among samples. Although we tried to resolve this issue and used FPRP to increase the reliability of the study results, the exact source of the heterogeneity still could not be completely explained. The present study also revealed that the heterogeneity was not from a single study. The differences in the distribution of the gene polymorphism frequency among ethnic groups and other unknown factors might be the real sources of the heterogeneity. Because gastrointestinal cancers are influenced by many factors, comprehensive study and analysis should be performed in the future by combining these factors, such as diet, living habits, and environmental exposure. Next, due to the restriction of the sample size and disease types in the included literature, we did not retrieve similar literature reports on other gastrointestinal cancers other than gastric cancer and colorectal cancer, and their association with the COX-2 -1195G>A gene polymorphism could not be clarified. Third, the present study is a meta-analysis based on the reported data of the included literature. The unreasonable data in the original studies could not be corrected and possible potential confounding factors, such as age, gender, ethnicity, specific living habits, and smoking and drinking habits, might be present. Fourth, all of the included literature was published in Chinese or English; relevant studies written in other languages may have been missed. Only including Chinese and English literature was also a reason that the sample size was not large enough, which might result in the presence of false-negative results. In addition, this meta-analysis only included published literature, and there are some relevant, important unpublished studies, which might cause a potential publication bias.

In summary, we demonstrate that the AA genotype in the COX-2 -1195G>A gene polymorphism might be an important predisposing factor for gastrointestinal cancers compared to the AG or GG phenotypes, especially for gastric cancer. In addition, compared to the included studies on American and European Caucasian populations, COX-2 -1195G>A increased susceptibility of the Asian population to gastrointestinal cancer. In the future, studies with larger sample sizes, more rational design, and more disease types should be performed to validate our conclusion, which can more clearly clarify the association between the COX-2 -1195G>A gene polymorphism and gastrointestinal cancers.

COMMENTS
Background

Cyclooxygenase-2 (COX-2) is closely associated with the development of malignant tumours and is highly expressed in gastric cancer and colorectal cancer cells. Many studies have investigated the association between the COX-2 -1195G>A gene polymorphism and gastrointestinal cancers; however, the results are inconsistent.

Research frontiers

The COX-2 gene is a very important tumour-related gene with multiple SNPs. The expression level of this gene and the function of its encoded protein will be affected by some polymorphic sites, thus increasing or decreasing tumour susceptibility.

Innovations and breakthroughs

In the present study, the authors explored the COX-2 -1195G>A gene polymorphisms associated with susceptibility to gastrointestinal cancers and used an FPRP-based criterion to evaluate whether the study finding was noteworthy.

Applications

This report may present a novel site for the prevention, diagnosis, and molecular targeted therapy of gastric cancer and colorectal cancer.

Terminology

The false positive report probability (FPRP), which is the probability of no true association between a genetic variant and disease given a statistically significant finding, depends not only on the observed P-value but also on both the prior probability and the statistical power of the test.

Peer-review

The authors performed a meta-analysis of the association between the COX-2 -1195G>A polymorphism and gastrointestinal cancer risk, which has been extensively investigated.

Footnotes

Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Saudi Arabia

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Ghiorzo P S- Editor: Ma YJ L- Editor: Wang TQ E- Editor: Wang CH

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