Chronic inflammation has been regarded as an important mechanism in carcinogenesis. Inflammation-associated genetic variants have been highly associated with cancer risk. Polymorphisms in the gene cyclooxygenase-2 (COX-2), a pro-inflammation factor, have been suggested to alter the risk of multiple tumors, but the findings of various studies are not consistent.
A literature search through February 2013 was performed using PubMed, EMBASE, and CNKI databases. We used odds ratios (ORs) with confidence intervals (CIs) of 95% to assess the strength of the association between the COX-2-765G>C polymorphism and cancer risk in a random-effect model. We also assessed heterogeneity and publication bias.
In total, 65 articles with 29,487 cancer cases and 39,212 non-cancer controls were included in this meta-analysis. The pooled OR (95% CIs) in the co-dominant model (GC vs. GG) was 1.11 (1.02–1.22), and in the dominant model ((CC+GC) vs. GG), the pooled OR was 1.12 (1.02–1.23). In the subgroup analysis, stratified by cancer type and race, significant associations were found between the-765 C allele and higher risk for gastric cancer, leukemia, pancreatic cancer, and cancer in the Asian population.
Citation: Wang X-f, Huang M-z, Zhang X-w, Hua R-x, Guo W-j (2013) COX-2-765G>C Polymorphism Increases the Risk of Cancer: A Meta-Analysis. PLoS ONE 8(9): e73213. doi:10.1371/journal.pone.0073213
Editor: Xiaoping Miao, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, China
Received: June 5, 2013; Accepted: July 18, 2013; Published: September 4, 2013
Copyright: © 2013 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by grants from the National Natural Scientific Funding (81171909). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Cancer is a complicated disease resulting from the combined effect of genetic susceptibility and external elements such as lifestyle and inflammation , . The role of inflammation in carcinogenesis is a pivotal issue. Studies have demonstrated that inflammation-associated molecules are associated with a majority of cancer types, and these molecules are activated by various elements related to environment and lifestyle . Signs of inflammation, including cytokines, chemokines, and immune cells, have been identified in many precancerous and cancerous tissues . Several models have typically demonstrated that inflammation induces certain cancers: chronic intestinal inflammation has been associated with colon cancer; Helicobacter pylori (HP) with gastric cancer; human papilloma virus (HPV) infection with cervical carcinoma; and hepatitis B virus (HBV) infection with hepatocellular carcinoma –. Chronic inflammation of the colon (e.g., ulcerative colitis) markedly increases the risk of developing colon cancer . The persistent presence of pathogenic microorganisms causes chronic inflammation that raises the likelihood of some cancers .
Cyclooxygenase-2 (COX-2), known as prostaglandin-endoperoxide synthase 2 (PTGS2), is a rate-limiting enzyme produced during the production of prostaglandins, and prostaglandins play an important role in inflammation, tumor progression, and metastasis . COX-2 is often undetectable in normal tissue, whereas in tumor tissue specimens its expression is observably higher . It has been reported that COX-2 overexpression contributes to carcinogenesis by increasing cell proliferation, suppressing apoptosis, enhancing invasiveness, and inducing chronic activation of immune responses , .
Genetic variants may affect the expression of COX-2, and the underlying mechanism is considered to occur through self-regulated transcriptional activity resulting from variations in the capability of its promoter region to bind with certain nuclear proteins . The single-nucleotide polymorphism (SNP) COX-2-765G>C (rs20417) is a functional, extensively studied polymorphism that features guanine (G) converting to cytosine (C) at position-765 bp of the promoter region, altering the transcription activity of the COX-2 gene. Several studies have demonstrated the COX-2-765 G>C polymorphism to be associated with increased risk of human cancers such as gastric cancer, colorectal cancer, prostate cancer, breast cancer, and others –. However, in other studies, the COX-2-765 C allele was not observed to be associated with cancer risk . To further ascertain the relationship between COX-2-765 G>C and cancer risk, several further meta-analyses were performed, but regrettably, the results among studies have varied for different cancer types –. Recently, additional studies of the COX-2-765 G>C polymorphism in several cancer types have been reported; therefore, we conducted this meta-analysis to synthesize the results of these studies and to establish a more durable conclusion.
A systematic literature search through February 12, 2013, was performed using the databases of PubMed and EMBASE and searching for the following terms: (cyclooxygenase-2 or COX-2 or PTGS2) and (polymorphism or polymorphisms or variant or variants or genotype) and (cancer or carcinoma or neoplasm). To expand our investigation, we also searched China National Knowledge Infrastructure (CNKI) database using the following terms in Chinese: COX-2, cancer risk, and polymorphism. References for these articles and eligible literature from review articles were also collected.
Inclusion and Exclusion Criteria and Data Extraction
Article selection for the meta-analysis used the following inclusion criteria: 1) information on the evaluation of COX-2-765G>C (rs20417) polymorphism and cancer risk; 2) case-controlled study; 3) human subjects; and 4) sufficient genotype data to calculate the odds ratios (ORs) with 95% confidence intervals (CIs). When the same or overlapping populations were included in several publications, the studies with larger sample size were selected. When pertinent data were not included or data presented were unclear, we contacted the authors to collect more data or to clarify the study results. Exclusion criteria were the following: 1) no controls; 2) overlapping study populations; 3) not enough pertinent data; and 4) departure from the Hardy-Weinberg equilibrium (HWE) method in control subjects.
The following data were extracted from all eligible publications: the first author, publication year, cancer type, country and race of the study population, control source (population-based (PB), hospital-based (HB) and family-based (FB)), total number of cases and controls studied, number of cases and controls with the wild-type, heterozygous, and homozygous genotypes, and with the minor allele frequency (MAF). Ethnic subgroups were categorized as Caucasian, Asian, American, and African. For case-control studies with subjects of different races, data were extracted separately for each ethnic group whenever possible. When a study did not include detailed genotypes of each ethnic group, or if it was difficult to discriminate the ethnicity of participants according to the data presented, the study was termed “mixed”. If the study was performed in different counties or regions and the subgroups were indistinguishable in the report, the study was termed “multicenter”. All data were independently extracted by two investigators according to these selection criteria. Disagreement was resolved by discussion.
We utilized odds ratios (ORs) with 95% (confidence intervals) CIs to assess the strength of association between the COX-2-765G>C polymorphism and cancer risk. The pooled ORs with 95% CIs were calculated in a co-dominant model (variant homozygote vs. heterozygote) and a dominant model (variant homozygote+heterozygote vs. wild-type homozygote). Subgroup analyses were stratified by ethnicity and cancer type.
We used the goodness-of-fit χ2 test to evaluate HWE for control subjects in each study, and we considered P<0.05 to representative significant departure from HWE . The heterogeneity assumption was verified using the χ2-based Q-test. Q-test results of P>0.05 suggested a lack of heterogeneity among studies, so the pooled OR of all studies was calculated using the fixed-effect model based on the Mantel–Haenszel method. Otherwise, we used the random-effect model, based on the DerSimonian–Laird method, which provides a larger pool of 95% CIs from studies differing among themselves , .
We also conducted a sensitivity analysis by excluding each study, one at a time, and recalculating the ORs and 95% CIs to assess the effects of each study on the pooled risk of cancer . Then we performed an estimate of potential publication bias using the funnel plot, in which the standard error of log (OR) of every study was plotted against its log (OR) , and an asymmetric plot indicated a potential publication bias. We assessed funnel-plot asymmetry using Egger’s linear regression test, a linear regression method of evaluating funnel plot asymmetry on the natural logarithm scale of the OR . The significance of the intercept was determined using the t-test suggested by Egger, and p<0.05 was considered representative of statistically significant publication bias , . In cases of publication bias, the Duval and Tweedie nonparametric ‘‘trim and fill.’’ method was performed to adjust for it . All of the statistical tests were performed using STATA version 10.0 (Stata Corporation, College Station, TX).
Eligible Studies Characteristics
A total of 579 publications from the MEDLINE, EMBASE, and CNKI databases were reviewed using the specified key words. After a review of titles and abstracts, 494 publications were excluded according to our criteria. From the remaining 85 studies on COX-2-765G>C polymorphism and susceptibility to cancer that met our inclusion criteria, we eliminated 5 publications due to insufficient genotype data, 11 due to deviation from Hardy-Weinberg equilibrium in controls, and 4 due to overlap with other studies. Finally, 65 articles, including with 29,487 cancer cases and 39,212 non-cancer controls, were included in this meta-analysis. A flow chart of the study selection procedure is shown in Fig. 1.
The main characteristics of the studies are listed in Table 1. The respective studies focused on the following cancer types: 13 studies investigated colorectal carcinoma , –, 9 gastric cancer , –, 8 prostate cancer , –, 6 esophageal cancer –, 3 colorectal adenoma –, 4 cancer of head and neck (HNC) –, 4 breast cancer , –, 3 lung cancer –, 3 lymphoma –, 3 skin cancer –, 2 leukemia , , 2 pancreatic cancer , , 2 ovarian cancer , , 2 hepatocellular carcinoma (HCC) , , 1 cervical cancer , 1 glioblastoma , and 1 combination of colorectal and esophageal cancers, which were indistinguishable . Twenty-five studies used Asian research subjects, 25 Caucasian, 9 American, 3 African, and 5 used mixed ethnic subjects. Thirty-five study designs were population based (PB), 31 were hospital based (HB), and 1 was family based (FB). The genotyping method used in most of the studies (56/67) was polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP).
The main results of the meta-analysis are listed in Table 2. The association between COX-2-765 G>C polymorphism and cancer risk was estimated in two comparison models: a co-dominant model (GC vs. GG) and a dominant model ((CC+GC) vs. GG). The analysis used a random pooling model because the heterogeneity among studies was significant in the co-dominant model and in the dominant model (p<0.001). In the co-dominant model, the overall pooled effect indicated that the-765 GC heterozygote was associated with a significantly increased overall cancer risk, compared with the GG homozygote (OR = 1.11, 95% CI = 1.02–1.22, P = 0.01). In stratification analyses by cancer type and ethnicity, the association was maintained in gastric cancer (OR = 1.53, 95% CI = 1.04–2.24, p = 0.03), leukemia (OR = 1.86, 95% CI = 1.32–2.62, P<0.01), pancreatic cancer (OR = 2.51, 95% CI = 1.73–3.66, P<0.01), and cancer in the Asian population (OR = 1.41, 95% CI = 1.16–1.72, p<0.01) (Fig. 2A and B). Notably, the association between the COX-2-765 C allele and decreased cancer risk was found in the Caucasian population (OR = 0.91, 95% CI = 0.83–1.00, P = 0.04). However, this difference may have been the result of different ethnic subjects and bias from different genotyping methods. In the dominant model, we found significant associations of this SNP with cancer risk in overall cancer susceptibility (OR = 1.12, 95% CI = 1.02–1.23, P = 0.01), gastric cancer (OR = 1.60, 95% CI = 1.02–2.50, P = 0.04), leukemia (OR = 1.91, 95% CI = 1.36–2.69, P<0.01), pancreatic cancer (OR = 2.51, 95% CI = 1.73–3.66, P<0.01), and cancer in the Asian population (OR = 1.42, 95% CI = 1.15–1.76, P<0.01) (Fig. 2C and D).
GC vs. GG in the co-dominant model by the random effects for (A) gastric cancer, leukemia, pancreatic cancer and (B) in the Asian population. (CC+GC) vs. GG in a dominant model by the random-effects for (C) gastric cancer, leukemia, pancreatic cancer and (D) in the Asian population.
Heterogeneity, Sensitivity Analysis, and Publication Bias
Heterogeneity was determined using the χ2-based Q-test, and heterogeneity was found in two pooling models (P<0.01 in both models), so the random model was utilized to generate a larger pool of studies with 95% CIs. We performed the sensitivity analysis by assessing the influence of an individual study on the overall OR. No individual study affected the pooled OR markedly, since omission of any single study made no substantial difference. Also, we conducted Begger’s funnel plot and Egger’s test to assess the publication bias of all eligible literature. The shapes of the funnel plot seemed symmetrical in two comparison models, and statistical results from Egger’s test still did not show publication bias (p = 0.36 in co-dominant model and p = 0.34 in dominant model). These findings demonstrated that publication bias, if any, did not significantly affect the results of our meta-analysis for the association between COX-2-765G>C and cancer risk.
COX-2-765G>C is a functional polymorphism, located at 765 bp upstream (-765 bp) from the transcription start site. It changes a putative stimulatory protein (Sp1) binding site in the promoter of COX-2 between-766 and-761 bp , but it creates an E2 promoter factor (E2F) binding site, leading to high transcription activity, which may be the mechanism of COX-2-765G>C polymorphism increasing cancer risk .
The current meta-analysis explored the role of COX-2-765G>C polymorphism in the susceptibility of cancer among 65 articles with 29487 cancer cases and 39212 non-cancer controls. We found that C-allele carriers had an increased risk of cancer, especially gastric cancer, leukemia, and pancreatic cancer and cancer in the Asia population, when compared with G carriers. Our results show that COX-2-765 C carriers are at significantly increased risk for gastric cancer, leukemia, and pancreatic cancer but not other cancer types. One possible explanation is that different types of cancer have various mechanism of carcinogenesis. Additionally, it is possible that the significant difference effects are casual, because studies with small sample sizes have deficient statistical power to disclose a slight effect. Interestingly, our meta-analysis revealed an association between the COX-2-765 C allele and decreased cancer risk in Caucasian population. In this Caucasian subgroup, a large study sample with 6254 cases and 8092 controls (two thirds of all subjects in this subgroup) showed an MAF (0.84)  significantly higher than in other reports, which may have affected the results. Additionally, this extremely high MAF value may have resulted from bias induced by experimental procedure and methods. Our study differed from previous meta-analyses in the subgroup analysis of gastric and colorectal cancer. Zhu reported a significant association between-765G>C polymorphisms and colorectal carcinoma, but not in gastric cancer, contrary to the results of our present study . In other studies, researchers analyzed the role of COX-2-765G>C polymorphism in diverse cancer types. No convincing association between the C allele and risk of prostate cancer , , breast cancer , and colorectal cancer  respectively, were revealed, but a significant association was reported between C allele and risks for gastric cancer  and esophageal cancer . However, the number of subjects included in previous studies was not as large, and our meta-analysis includes the latest studies. Furthermore, we analyzed at least twice as many studies as meta-analyses published previously . In summary, our findings provide the most current and powerful conclusion among analyses of this type.
Limitations encountered in this analysis should be considered as these results are interpreted. First, the CC genotype frequency in many studies was zero, so we assumed a co-dominant model and a dominant model. For some polymorphisms, this model might not be the most suitable for a clear assessment of the gene–disease interaction. Secondly, the results of the subgroup stratification analysis must be interpreted with caution because of the limited number of published studies. For example, only two reports for leukemia and pancreatic cancer were included. Thirdly, there is marked heterogeneity among studies in overall and some subgroup analyses, which may derive from ethnic groups and types of cancer, may have skewed our results. Finally, this systematic review was based on unadjusted data, as the genotype information stratified for the main confounding variables was not available in the original papers and the confounding factors addressed across the different studies varied. Adjusted estimates might provide more precise and stronger associations, as they reduced the impact of possible confounding factors. To determine a precise association between the COX-2-765G>C and cancer genetic susceptibility, it is essential to design and perform scientific and rigorous studies with large sample sizes in the future.
Although further research is needed, this present meta-analysis validates a significant association between COX-2-765G>C polymorphism and genetic cancer susceptibility, especially in gastric cancer, leukemia, pancreatic cancer, and cancer in the Asian population. If confirmed in future studies, this genotype may be used by clinicians to select individuals for early diagnosis and treatments.
Conceived and designed the experiments: WG. Wrote the paper: XW MH. Extracted and analyzed the data: XW MH. Polished the English writing: XZ RH.
- 1. Yaghoobi M, Rakhshani N, Sadr F, Bijarchi R, Joshaghani Y, et al. (2004) Hereditary risk factors for the development of gastric cancer in younger patients. BMC Gastroenterol 4: 28.
- 2. Berlau J, Glei M, Pool-Zobel BL (2004) Colon cancer risk factors from nutrition. Anal Bioanal Chem 378: 737–743.
- 3. Sethi G, Shanmugam MK, Ramachandran L, Kumar AP, Tergaonkar V (2012) Multifaceted link between cancer and inflammation. Biosci Rep 32: 1–15.
- 4. Mantovani A (2005) Cancer: inflammation by remote control. Nature 435: 752–753.
- 5. Rubin DC, Shaker A, Levin MS (2012) Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Front Immunol 3: 107.
- 6. Arzumanyan A, Reis HM, Feitelson MA (2013) Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 13: 123–135.
- 7. Haghshenas M, Golini-Moghaddam T, Rafiei A, Emadeian O, Shykhpour A, et al. (2013) Prevalence and type distribution of high-risk human papillomavirus in patients with cervical cancer: a population-based study. Infect Agent Cancer 8: 20.
- 8. Hardbower DM, de Sablet T, Chaturvedi R, Wilson KT (2013) Chronic inflammation and oxidative stress: The smoking gun for Helicobacter pylori-induced gastric cancer? Gut Microbes 4.
- 9. Ekbom A, Helmick C, Zack M, Adami HO (1990) Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 323: 1228–1233.
- 10. Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3: 276–285.
- 11. Wang MT, Honn KV, Nie D (2007) Cyclooxygenases, prostanoids, and tumor progression. Cancer Metastasis Rev 26: 525–534.
- 12. Cao Y, Prescott SM (2002) Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 190: 279–286.
- 13. O’Byrne KJ, Dalgleish AG (2001) Chronic immune activation and inflammation as the cause of malignancy. Br J Cancer 85: 473–483.
- 14. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, et al. (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93: 705–716.
- 15. Szczeklik W, Sanak M, Szczeklik A (2004) Functional effects and gender association of COX-2 gene polymorphism G-765C in bronchial asthma. J Allergy Clin Immunol 114: 248–253.
- 16. Zhang XM, Zhong R, Liu L, Wang Y, Yuan JX, et al. (2011) Smoking and COX-2 functional polymorphisms interact to increase the risk of gastric cardia adenocarcinoma in Chinese population. PLoS One 6: e21894.
- 17. Andersen V, Ostergaard M, Christensen J, Overvad K, Tjonneland A, et al. (2009) Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study. BMC Cancer 9: 407.
- 18. Balistreri CR, Caruso C, Carruba G, Miceli V, Campisi I, et al. (2010) A pilot study on prostate cancer risk and pro-inflammatory genotypes: pathophysiology and therapeutic implications. Curr Pharm Des 16: 718–724.
- 19. Cox DG, Buring J, Hankinson SE, Hunter DJ (2007) A polymorphism in the 3’ untranslated region of the gene encoding prostaglandin endoperoxide synthase 2 is not associated with an increase in breast cancer risk: a nested case-control study. Breast Cancer Res 9: R3.
- 20. Liu JL, Liang Y, Wang ZN, Zhou X, Xing LL (2010) Cyclooxygenase-2 polymorphisms and susceptibility to gastric carcinoma: a meta-analysis. World J Gastroenterol 16: 5510–5517.
- 21. Yu KD, Chen AX, Yang C, Qiu LX, Fan L, et al. (2010) Current evidence on the relationship between polymorphisms in the COX-2 gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 122: 251–257.
- 22. Dong J, Dai J, Zhang M, Hu Z, Shen H (2010) Potentially functional COX-2–1195G>A polymorphism increases the risk of digestive system cancers: a meta-analysis. J Gastroenterol Hepatol 25: 1042–1050.
- 23. Song Q, Zhu B, Hu W, Cheng L, Gong H, et al. (2012) A common SMAD7 variant is associated with risk of colorectal cancer: evidence from a case-control study and a meta-analysis. PLoS One 7: e33318.
- 24. Ma Y, Xu YC, Tang L, Zhang Z, Wang J, et al. (2012) Cytokine-induced killer (CIK) cell therapy for patients with hepatocellular carcinoma: efficacy and safety. Exp Hematol Oncol 1: 11.
- 25. Chen W, Zhong R, Ming J, Zou L, Zhu B, et al. (2012) The SLC4A7 variant rs4973768 is associated with breast cancer risk: evidence from a case-control study and a meta-analysis. Breast Cancer Res Treat 136: 847–857.
- 26. Ke J, Zhong R, Zhang T, Liu L, Rui R, et al. (2013) Replication study in Chinese population and meta-analysis supports association of the 5p15.33 locus with lung cancer. PLoS One 8: e62485.
- 27. Wei G, Ni W, Chiao JW, Cai Z, Huang H, et al. (2011) A meta-analysis of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome. J Hematol Oncol 4: 46.
- 28. Liu L, Yuan P, Liu L, Wu C, Zhang X, et al. (2011) A functional-77T>C polymorphism in XRCC1 is associated with risk of breast cancer. Breast Cancer Res Treat 125: 479–487.
- 29. Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634.
- 30. Liu L, Wu J, Wu C, Wang Y, Zhong R, et al. (2011) A functional polymorphism (-1607 1G–>2G) in the matrix metalloproteinase-1 promoter is associated with development and progression of lung cancer. Cancer 117: 5172–5181.
- 31. Duval S, Tweedie R (2000) Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56: 455–463.
- 32. Tan W, Wu J, Zhang X, Guo Y, Liu J, et al. (2007) Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer. Carcinogenesis 28: 1197–1201.
- 33. Xing LL, Wang ZN, Jiang L, Zhang Y, Xu YY, et al. (2008) Cyclooxygenase 2 polymorphism and colorectal cancer:-765G>C variant modifies risk associated with smoking and body mass index. World J Gastroenterol 14: 1785–1789.
- 34. Koh WP, Yuan JM, van den Berg D, Lee HP, Yu MC (2004) Interaction between cyclooxygenase-2 gene polymorphism and dietary n-6 polyunsaturated fatty acids on colon cancer risk: the Singapore Chinese Health Study. Br J Cancer 90: 1760–1764.
- 35. Iglesias D, Nejda N, Azcoita MM, Schwartz SJ, Gonzalez-Aguilera JJ, et al. (2009) Effect of COX2–765G>C and c.3618A>G polymorphisms on the risk and survival of sporadic colorectal cancer. Cancer Causes Control 20: 1421–1429.
- 36. Gong Z, Bostick RM, Xie D, Hurley TG, Deng Z, et al. (2009) Genetic polymorphisms in the cyclooxygenase-1 and cyclooxygenase-2 genes and risk of colorectal adenoma. Int J Colorectal Dis 24: 647–654.
- 37. Wang J, Joshi AD, Corral R, Siegmund KD, Marchand LL, et al. (2012) Carcinogen metabolism genes, red meat and poultry intake, and colorectal cancer risk. Int J Cancer 130: 1898–1907.
- 38. Daraei A, Salehi R, Mohamadhashem F (2012) PTGS2 (COX2)-765G>C gene polymorphism and risk of sporadic colorectal cancer in Iranian population. Mol Biol Rep 39: 5219–5224.
- 39. Cox DG, Pontes C, Guino E, Navarro M, Osorio A, et al. (2004) Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer. Br J Cancer 91: 339–343.
- 40. Hoff JH, Te MR, Roelofs HM, van der Logt EM, Nagengast FM, et al. (2009) COX-2 polymorphisms-765G–>C and-1195A–>G and colorectal cancer risk. World J Gastroenterol 15: 4561–4565.
- 41. Pereira C, Pimentel-Nunes P, Brandao C, Moreira-Dias L, Medeiros R, et al. (2010) COX-2 polymorphisms and colorectal cancer risk: a strategy for chemoprevention. Eur J Gastroenterol Hepatol 22: 607–613.
- 42. Hamajima N, Takezaki T, Matsuo K, Saito T, Inoue M, et al. (2001) Genotype Frequencies of Cyclooxygenease 2 (COX2) Rare Polymorphisms for Japanese with and without Colorectal Cancer. Asian Pac J Cancer Prev 2: 57–62.
- 43. Thompson CL, Plummer SJ, Merkulova A, Cheng I, Tucker TC, et al. (2009) No association between cyclooxygenase-2 and uridine diphosphate glucuronosyltransferase 1A6 genetic polymorphisms and colon cancer risk. World J Gastroenterol 15: 2240–2244.
- 44. Li Y, Dai L, Zhang J, Wang P, Chai Y, et al. (2012) Cyclooxygenase-2 polymorphisms and the risk of gastric cancer in various degrees of relationship in the Chinese Han population. Oncol Lett 3: 107–112.
- 45. Hou L, Grillo P, Zhu ZZ, Lissowska J, Yeager M, et al. (2007) COX1 and COX2 polymorphisms and gastric cancer risk in a Polish population. Anticancer Res 27: 4243–4247.
- 46. Shin WG, Kim HJ, Cho SJ, Kim HS, Kim KH, et al. (2012) The COX-2–1195AA Genotype Is Associated with Diffuse-Type Gastric Cancer in Korea. Gut Liver 6: 321–327.
- 47. Liu F, Pan K, Zhang X, Zhang Y, Zhang L, et al. (2006) Genetic variants in cyclooxygenase-2: Expression and risk of gastric cancer and its precursors in a Chinese population. Gastroenterology 130: 1975–1984.
- 48. Sitarz R, Leguit RJ, de Leng WW, Polak M, Morsink FM, et al. (2008) The COX-2 promoter polymorphism-765 G>C is associated with early-onset, conventional and stump gastric cancers. Mod Pathol 21: 685–690.
- 49. Pereira C, Sousa H, Ferreira P, Fragoso M, Moreira-Dias L, et al. (2006) -765G>C COX-2 polymorphism may be a susceptibility marker for gastric adenocarcinoma in patients with atrophy or intestinal metaplasia. World J Gastroenterol 12: 5473–5478.
- 50. Saxena A, Prasad KN, Ghoshal UC, Bhagat MR, Krishnani N, et al. (2008) Polymorphism of-765G>C COX-2 is a risk factor for gastric adenocarcinoma and peptic ulcer disease in addition to H pylori infection: a study from northern India. World J Gastroenterol 14: 1498–1503.
- 51. Bi N, Yang M, Zhang L, Chen X, Ji W, et al. (2010) Cyclooxygenase-2 genetic variants are associated with survival in unresectable locally advanced non-small cell lung cancer. Clin Cancer Res 16: 2383–2390.
- 52. Cheng I, Liu X, Plummer SJ, Krumroy LM, Casey G, et al. (2007) COX2 genetic variation, NSAIDs, and advanced prostate cancer risk. Br J Cancer 97: 557–561.
- 53. Murad A, Lewis SJ, Smith GD, Collin SM, Chen L, et al. (2009) PTGS2–899G>C and prostate cancer risk: a population-based nested case-control study (ProtecT) and a systematic review with meta-analysis. Prostate Cancer Prostatic Dis 12: 296–300.
- 54. Catsburg C, Joshi AD, Corral R, Lewinger JP, Koo J, et al. (2012) Polymorphisms in carcinogen metabolism enzymes, fish intake, and risk of prostate cancer. Carcinogenesis 33: 1352–1359.
- 55. Wu HC, Chang CH, Ke HL, Chang WS, Cheng HN, et al. (2011) Association of cyclooxygenase 2 polymorphic genotypes with prostate cancer in taiwan. Anticancer Res 31: 221–225.
- 56. Joshi AD, Corral R, Catsburg C, Lewinger JP, Koo J, et al. (2012) Red meat and poultry, cooking practices, genetic susceptibility and risk of prostate cancer: results from a multiethnic case-control study. Carcinogenesis 33: 2108–2118.
- 57. Panguluri RC, Long LO, Chen W, Wang S, Coulibaly A, et al. (2004) COX-2 gene promoter haplotypes and prostate cancer risk. Carcinogenesis 25: 961–966.
- 58. Kristinsson JO, van Westerveld P, Te MR, Roelofs HM, Wobbes T, et al. (2009) Cyclooxygenase-2 polymorphisms and the risk of esophageal adeno- or squamous cell carcinoma. World J Gastroenterol 15: 3493–3497.
- 59. Upadhyay R, Jain M, Kumar S, Ghoshal UC, Mittal B (2009) Functional polymorphisms of cyclooxygenase-2 (COX-2) gene and risk for esophageal squmaous cell carcinoma. Mutat Res 663: 52–59.
- 60. Zhang X, Miao X, Tan W, Ning B, Liu Z, et al. (2005) Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology 129: 565–576.
- 61. Moons LM, Kuipers EJ, Rygiel AM, Groothuismink AZ, Geldof H, et al. (2007) COX-2 CA-haplotype is a risk factor for the development of esophageal adenocarcinoma. Am J Gastroenterol 102: 2373–2379.
- 62. Bye H, Prescott NJ, Matejcic M, Rose E, Lewis CM, et al. (2011) Population-specific genetic associations with oesophageal squamous cell carcinoma in South Africa. Carcinogenesis 32: 1855–1861.
- 63. Ulrich CM, Whitton J, Yu JH, Sibert J, Sparks R, et al. (2005) PTGS2 (COX-2)-765G>C promoter variant reduces risk of colorectal adenoma among nonusers of nonsteroidal anti-inflammatory drugs. Cancer Epidemiol Biomarkers Prev 14: 616–619.
- 64. Ueda N, Maehara Y, Tajima O, Tabata S, Wakabayashi K, et al. (2008) Genetic polymorphisms of cyclooxygenase-2 and colorectal adenoma risk: the Self Defense Forces Health Study. Cancer Sci 99: 576–581.
- 65. Gunter MJ, Canzian F, Landi S, Chanock SJ, Sinha R, et al. (2006) Inflammation-related gene polymorphisms and colorectal adenoma. Cancer Epidemiol Biomarkers Prev 15: 1126–1131.
- 66. Peters WH, Lacko M, Te MR, Voogd AC, Oude OM, et al. (2009) COX-2 polymorphisms and the risk for head and neck cancer in white patients. Head Neck 31: 938–943.
- 67. Ben NH, Chahed K, Bouaouina N, Chouchane L (2009) PTGS2 (COX-2)-765 G>C functional promoter polymorphism and its association with risk and lymph node metastasis in nasopharyngeal carcinoma. Mol Biol Rep 36: 193–200.
- 68. Mittal M, Kapoor V, Mohanti BK, Das SN (2010) Functional variants of COX-2 and risk of tobacco-related oral squamous cell carcinoma in high-risk Asian Indians. Oral Oncol 46: 622–626.
- 69. Chiang SL, Chen PH, Lee CH, Ko AM, Lee KW, et al. (2008) Up-regulation of inflammatory signalings by areca nut extract and role of cyclooxygenase-2–1195G>a polymorphism reveal risk of oral cancer. Cancer Res 68: 8489–8498.
- 70. Gao J, Ke Q, Ma HX, Wang Y, Zhou Y, et al. (2007) Functional polymorphisms in the cyclooxygenase 2 (COX-2) gene and risk of breast cancer in a Chinese population. J Toxicol Environ Health A 70: 908–915.
- 71. Piranda DN, Festa-Vasconcellos JS, Amaral LM, Bergmann A, Vianna-Jorge R (2010) Polymorphisms in regulatory regions of cyclooxygenase-2 gene and breast cancer risk in Brazilians: a case-control study. BMC Cancer 10: 613.
- 72. Dossus L, Kaaks R, Canzian F, Albanes D, Berndt SI, et al. (2010) PTGS2 and IL6 genetic variation and risk of breast and prostate cancer: results from the Breast and Prostate Cancer Cohort Consortium (BPC3). Carcinogenesis 31: 455–461.
- 73. Coskunpinar E, Eraltan IY, Turna A, Agachan B (2011) Cyclooxygenase-2 gene and lung carcinoma risk. Med Oncol 28: 1436–1440.
- 74. Campa D, Zienolddiny S, Maggini V, Skaug V, Haugen A, et al. (2004) Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis 25: 229–235.
- 75. Liu CJ, Hsia TC, Wang RF, Tsai CW, Chu CC, et al. (2010) Interaction of cyclooxygenase 2 genotype and smoking habit in Taiwanese lung cancer patients. Anticancer Res 30: 1195–1199.
- 76. Hoeft B, Becker N, Deeg E, Beckmann L, Nieters A (2008) Joint effect between regular use of non-steroidal anti-inflammatory drugs, variants in inflammatory genes and risk of lymphoma. Cancer Causes Control 19: 163–173.
- 77. Monroy CM, Cortes AC, Lopez MS, D’Amelio AJ, Etzel CJ, et al. (2011) Hodgkin disease risk: role of genetic polymorphisms and gene-gene interactions in inflammation pathway genes. Mol Carcinog 50: 36–46.
- 78. Chang ET, Birmann BM, Kasperzyk JL, Conti DV, Kraft P, et al. (2009) Polymorphic variation in NFKB1 and other aspirin-related genes and risk of Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 18: 976–986.
- 79. Lira MG, Mazzola S, Tessari G, Malerba G, Ortombina M, et al. (2007) Association of functional gene variants in the regulatory regions of COX-2 gene (PTGS2) with nonmelanoma skin cancer after organ transplantation. Br J Dermatol 157: 49–57.
- 80. Cocos R, Schipor S, Nicolae I, Thomescu C, Raicu F (2012) Role of COX-2 activity and CRP levels in patients with non-melanoma skin cancer.-765G>C PTGS2 polymorphism and NMSC risk. Arch Dermatol Res 304: 335–342.
- 81. Vogel U, Christensen J, Wallin H, Friis S, Nexo BA, et al. (2007) Polymorphisms in COX-2, NSAID use and risk of basal cell carcinoma in a prospective study of Danes. Mutat Res 617: 138–146.
- 82. Wang CH, Wu KH, Yang YL, Peng CT, Wang RF, et al. (2010) Association study of cyclooxygenase 2 single nucleotide polymorphisms and childhood acute lymphoblastic leukemia in Taiwan. Anticancer Res 30: 3649–3653.
- 83. Zheng J, Chen S, Jiang L, You Y, Wu D, et al. (2011) Functional genetic variations of cyclooxygenase-2 and susceptibility to acute myeloid leukemia in a Chinese population. Eur J Haematol 87: 486–493.
- 84. Zhao D, Xu D, Zhang X, Wang L, Tan W, et al. (2009) Interaction of cyclooxygenase-2 variants and smoking in pancreatic cancer: a possible role of nucleophosmin. Gastroenterology 136: 1659–1668.
- 85. Xu DK, Zhang XM, Zhao P, Cai JC, Zhao D, et al. (2008) [Association between single nucleotide polymorphisms in the promoter of cyclooxygenase COX-2 gene and hereditary susceptibility to pancreatic cancer]. Zhonghua Yi Xue Za Zhi 88: 1961–1965.
- 86. Agachan CB, Attar R, Kahraman OT, Dalan AB, Iyibozkurt AC, et al. (2011) Cyclooxygenase-2 gene and epithelial ovarian carcinoma risk. Mol Biol Rep 38: 3481–3486.
- 87. Pinheiro SP, Gates MA, DeVivo I, Rosner BA, Tworoger SS, et al. (2010) Interaction between use of non-steroidal anti-inflammatory drugs and selected genetic polymorphisms in ovarian cancer risk. Int J Mol Epidemiol Genet 1: 320–331.
- 88. Chang WS, Yang MD, Tsai CW, Cheng LH, Jeng LB, et al. (2012) Association of cyclooxygenase 2 single-nucleotide polymorphisms and hepatocellular carcinoma in Taiwan. Chin J Physiol 55: 1–7.
- 89. He J, Zhang Q, Ren Z, Li Y, Li X, et al. (2012) Cyclooxygenase-2–765 G/C polymorphisms and susceptibility to hepatitis B-related liver cancer in Han Chinese population. Mol Biol Rep 39: 4163–4168.
- 90. Pandey S, Mittal RD, Srivastava M, Srivastava K, Mittal B (2010) Cyclooxygenase-2 gene polymorphisms and risk of cervical cancer in a North Indian population. Int J Gynecol Cancer 20: 625–630.
- 91. Schwartzbaum J, Ahlbom A, Malmer B, Lonn S, Brookes AJ, et al. (2005) Polymorphisms associated with asthma are inversely related to glioblastoma multiforme. Cancer Res 65: 6459–6465.
- 92. Biramijamal F, Basatvat S, Hossein-Nezhad A, Soltani MS, Akbari NK, et al. (2010) Association of COX-2 promoter polymorphism with gastrointestinal tract cancer in Iran. Biochem Genet 48: 915–923.
- 93. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, et al. (2002) Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 22: 1631–1636.
- 94. Zhu W, Wei BB, Shan X, Liu P (2010) -765G>C and 8473T>C polymorphisms of COX-2 and cancer risk: a meta-analysis based on 33 case-control studies. Mol Biol Rep 37: 277–288.
- 95. Zhang HT, Xu Y, Zhang ZH, Li L (2012) Meta-analysis of epidemiological studies demonstrates significant association of PTGS2 polymorphism rs689470 and no significant association of rs20417 with prostate cancer. Genet Mol Res 11: 1642–1650.
- 96. Cao H, Xu Z, Long H, Li XQ, Li SL (2010) The-765C allele of the cyclooxygenase-2 gene as a potential risk factor of colorectal cancer: a meta-analysis. Tohoku J Exp Med 222: 15–21.
- 97. Pereira C, Medeiros RM, Dinis-Ribeiro MJ (2009) Cyclooxygenase polymorphisms in gastric and colorectal carcinogenesis: are conclusive results available? Eur J Gastroenterol Hepatol 21: 76–91.
- 98. Liang Y, Liu JL, Wu Y, Zhang ZY, Wu R (2011) Cyclooxygenase-2 polymorphisms and susceptibility to esophageal cancer: a meta-analysis. Tohoku J Exp Med 223: 137–144.