Tao Li, Xiyan Mu, Ce Bian, Fan Yang, Shengtao Zhou, An Tong, Heng Zheng, Xia Zhao

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1 Int J Clin Exp Pathol 2016;9(7): /ISSN: /IJCEP Review Article Interleukin 17 rs and rs gene polymorphisms and women s cancer risk in Chinese population: a systemic review and meta-analysis Tao Li, Xiyan Mu, Ce Bian, Fan Yang, Shengtao Zhou, An Tong, Heng Zheng, Xia Zhao Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu , Sichuan, PR China Received May 1, 2016; Accepted May 19, 2016; Epub July 1, 2016; Published July 15, 2016 Abstract: The aim of this study was to evaluate interleukin 17 (IL-17) rs and rs gene polymorphisms in women s cancer risk of Chinese population by meta-analysis. A comprehensive electronic search was conducted in PubMed, Weipu, Medline (Ovid), Embase, Wanfang and CNKI. The pooled ORs were performed using the Revman 5.2 softerware. 5 articles including 9 case-control studies analyzing cervical cancer, breast cancer and ovarian cancer were included. The results showed significant association between IL-17 rs polymorphisms and the risk of women s cancer (AA vs. AG+GG: overall OR = 1.66, 95% CI = ; AA+AG vs. GG: overall OR = 1.38, 95% CI = ; AA vs. GG: overall OR = 1.93, 95% CI = ; A vs. G: overall OR = 1.35, 95% CI = ). No association was found in rs gene polymorphisms with women s cancer risk (CC vs. CT+TT: overall OR = 1.33, 95% CI = ; CC+CT vs. TT: overall OR = 1.54, 95% CI = ; CT vs. CC+TT: overall OR = 1.06, 95% CI = ; CC vs. TT: overall OR = 1.37, 95% CI = ; C vs. T: overall OR = 1.13, 95% CI = ). The subgroup results on cervical cancer were consistent with those of overall analysis. This metaanalysis suggested that IL-17 rs instead of rs polymorphisms were associated with the risks of women s cancer in Chinese people. Further studies are needed to validate the conclusion. Keywords: Interleukin 17, polymorphism, cervical, ovarian, breast, cancer Introduction Breast cancer, cervical cancer and ovarian cancer are the three most common malignancies in women [1-3]. While breast cancer has the highest morbidity among all types of women s cancer worldwide, cervical cancer is a leading cause of cancer death in Chinese women [4]. Ovarian cancer is the most deadly in gynecological malignancies, and more than half of women are diagnosed with ovarian cancer at an advanced stage [5]. The etiology of women s cancer is complicated and not completely understood. Estrogen and relevant metabolic factors have been widely explored but recent researches have focused on the roles of immunity and inflammation. Previous studies have found overexpression of interleukins in breast cancer and accumulating evidence showed that a series of cytokines including IL-1, IL-6, and IL-12 were associated with the development of cervical cancer [6-9]. Collectively, these findings strongly suggest that interleukin discrepancies may affect susceptibility to women s cancer. IL-17 is a novel pro-inflammatory cytokine family and has a critical role in innate and adaptive immune systems [10]. There are six family members in IL-17 (from IL-17A to IL-17F) where IL-17A and IL-17F are the most widely reported. IL-17A and IL-17F lie immediately adjacent to one another on human chromosome 6, and both cytokines are produced by Th17 cells in response to IL-23 [11-14]. Previous studies have revealed aberrant expressions of IL-17 in many human tumors, such as ovarian cancer, breast cancer, cervical cancer, esophageal cancer, gastric cancer, and colorectal cancer [15-20]. Thus, it is assumed that IL-17 polymor-

2 phisms, which can potentially cause alterations in their biological function, should contribute to the susceptibility of individuals to these cancers. The most widely studied polymorphisms of IL-17 were rs in IL-17A and rs in IL-17F. Several researches have been conducted to explore the relationship between rs and rs gene polymorphisms and risks of cancer [21, 22]. One meta-analysis reported that IL-17A rs G/A polymorphism was associated with elevated gastric cancer risk [23]. However, whether these polymorphisms play a role in women s cancer still remains to be solved. Thus, we performed a meta-analysis of currently relevant studies to investigate IL-17 rs and rs gene polymorphisms in risks of women s cancer. Materials and methods Literature and search strategy A comprehensive electronic search was performed in PubMed, Weipu, Medline (Ovid), Embase, Wanfang and CNKI for studies published from January 1996 to May The following search query was used: interleukin 17, IL-17, variant, mutation, polymorphism, cervical cancer, endometrial cancer, vulvar cancer, ovarian cancer and breast cancer. The search was updated every week until May 1st, Inclusion and exclusion criteria Articles fulfilling the following criteria were included: (i) analyzed IL-17 rs and rs polymorphisms in women s cancers (cervical cancer, endometrial cancer, vulvar cancer, ovarian cancer and breast cancer), (ii) provided sufficient data to calculate the odds ratios (ORs) and the corresponding 95% CIs in both case and control groups, (iii) case-control studies. When duplicate data were present in different articles, only the latest one would be included. Articles that didn t fulfill the criteria above were excluded. Data extraction and quality assessment Two researchers independently investigated all potential studies. The following data were extracted: first author, year of publication, cancer types, target genotypes, genotyping methods, cancer stage, features of control, participant numbers, genotype distributions and in cases and controls. Possible risk factors including menarche age, primiparity age, menopausal state, birth times, tobacco and alcohol habits, family history of cancer and HPV infection were also reviewed among participants. Any discrepancies were resolved by discussion with a third researcher until a consensus was reached. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of included studies. 3 aspects of selection, comparability, and exposure with 9 scores in total were carefully investigated. Studies with medium or high quality were included (score 5 and above) [24]. Statistical analysis Pooled ORs and corresponding 95% CIs were calculated to assess the strength of the association between the IL-17 rs and rs polymorphisms and the risks of cervical cancer, endometrial cancer, ovarian cancer and breast cancer. SNPs were considered as binary variables. For IL-17 rs polymorphisms, we estimated the risks of homozygous mutants (AA vs. AG+GG), heterozygous and homozygous mutants (AA+AG vs. GG) and heterozygous mutants (AG vs. AA+GG). We then compared the variant genotype AA with the wild type GG homozygote (AA vs. GG). We also assessed the risks of variant gene A alone. (A vs. G). As for IL-17 rs polymorphisms, we assessed CC vs. CT+TT, CC+CT vs. TT, CT vs. CC+TT, CC vs. TT and C vs. T. Heterogeneity was calculated using the Higgins I 2 test. If heterogeneity did not exist (I 2 <50%), a fixed-effects model was used otherwise a random-effects model was applied. The Z test was performed to determine the significance of the pooled ORs where P<0.05 was considered statistically significant [25]. The presence of publication bias was evaluated by inspecting the asymmetry in funnel plots visually. All analyses were performed using the Revman 5.2 softerware (Cochrane Collaboration, Copenhagen). Results Search results 78 results returned after the initial search. In our further review, 58 studies were excluded for 6627 Int J Clin Exp Pathol 2016;9(7):

3 Figure 1. The flow chart of study selection. Table 1. The characteristics of included studies First author Year Cancer reviews or non-clinical studies based on titles and abstracts. Among the remaining 15 articles, 9 studies were excluded for addressing other types of cancer such as gastric cancer, bladder cancer and thyroid cancer; 5 studies reported other interleukin polymorphisms like IL-1, IL-10 and IL-6; 1 study was excluded for not reporting rs and rs polymorphisms. Therefore, we enrolled 5 articles in this meta-analysis (Figure 1). Study characteristics Polymorphism Genotyping method 5 articles were enrolled: 3 for cervical cancer, 1 for breast cancer and 1 for ovarian cancer, all of which were on Chinese population, although in different provinces [26-30]. 2 were of medium quality (NOS score 6 or 7) and 3 were high Case stage Patient source of control Study quality (NOS) Lv 2015 Cervical rs PCR-RFLP I-IV Population 9 Quan 2012 Cervical rs PCR-RFLP I-III Population 6 Sun 2015 Cervical rs PCR-RFLP I-IV Hospital 8 Wang 2012 Breast rs SNaPshot I-IV Population 7 Ruan 2012 Ovarian rs PCR-RFLP N/A Hospital 8 Lv 2015 Cervical rs PCR-RFLP I-IV Population 9 Quan 2012 Cervical rs PCR-RFLP I-III Population 6 Sun 2015 Cervical rs PCR-RFLP I-IV Hospital 8 Wang 2012 Breast rs SNaPshot I-IV Population 7 Ruan 2012 Ovarian rs PCR-RFLP N/A Hospital 8 (NOS score 8 and 9) in quality. 1 study reported IL-17 polymorphisms of rs , rs , rs , rs763780, rs and rs in both case and control groups while the remaining 4 only reported rs and rs studies compared allele A with G in rs polymorphisms and C with T in rs polymorphisms while the other 1 considered allele A and G as variants in both rs and rs polymorphisms [30]. Thus, 9 case-control studies in all 5 articles were identified (Table 1). Possible variables among participants that might affect the odds ratios were also discussed including menarche age, primiparity age, menopausal state, birth times, tobacco and alcohol habits, family history of cancer and HPV infection (Table 2). Quantitative data analysis IL-17 rs polymorphisms and women s cancer: Tables 3 and 4 showed the pooled data of IL-17 rs polymorphisms in women s cancers. 3,084 participants were analyzed for overall risk and 1,962 participants were calculated for cervical cancer risk alone. We found significant association using 4 different genotype or allele comparisons in both overall groups (AA vs. AG+GG: overall OR = 1.66, 95% CI = ; AA+AG vs. GG: overall OR = 1.38, 95% CI = ; AA vs. GG: overall OR = 1.93, 95% CI = ; A vs. G: overall OR = 1.35, 95% CI = ) and cervical cancer subgroups (AA vs. AG+GG: cervical OR = 1.83, 95% CI = ; AA+AG vs. GG: cervical OR = 1.47, 95% CI = ; cervical AA vs. GG: OR = 2.11, 95% CI = ; A vs. G: cervical OR = 1.43, 95% CI = ). However, heterozygous mutants alone failed to 6628 Int J Clin Exp Pathol 2016;9(7):

4 Table 2. Comparison of possible risk factors between cases and controls First author Age Menarche age Primiparity age Menopausal state Birth times Smoking Alcohol Family history of cancer HPV-16 or -18 infection Lv NO N/A NO NO N/A NO NO NO YES Quan N/A N/A N/A N/A N/A N/A N/A N/A N/A Sun NO NO N/A NO NO NO NO NO YES Wang NO N/A N/A N/A N/A N/A N/A NO N/A Ruan NO NO N/A NO NO N/A N/A NO N/A NO: no difference presented between cases and controls. Yes: significant difference presented between cases and controls. Table 3. Genotype distributions in cases and controls First author Year Polymorphism Case number Control number *GG or TT AG or CT Case AA or CC G or T A or C GG or TT AG or CT Control AA or CC Lv 2015 rs Quan 2012 rs Sun 2015 rs Wang 2012 rs Ruan 2012 rs Lv 2015 rs Quan 2012 rs Sun 2015 rs Wang 2012 rs Ruan 2012 rs *Genotypes in rs polymorphisms were GG, AG, AA, G and A, and genotypes in rs polymorphisms were TT, CT, CC, T and C except Ruan 2012, where both rs and rs polymorphisms were GG, AG, AA, G and A. G or T A or C Table 4. Summary of different comparative results Polymorphism Genotypes Overall & subgroup Participants OR (95% CI) Z value P value I2 (%) Effect Model rs AA vs. AG+GG Overall 3, (1.21, 2.27) Random Cervical 1, (1.39, 2.41) 4.35 < Fixed AA+AG vs. GG Overall 3, (1.19, 1.60) 4.26 < Fixed Cervical 1, (1.22, 1.76) 4.08 < Fixed AG vs. AA+GG Overall 3, (0.90, 1.20) Fixed Cervical 1, (0.90, 1.29) Fixed AA vs. GG Overall 1, (1.54, 2.42) 5.72 < Fixed Cervical 1, (1.59, 2.81) 5.12 < Fixed A vs. G Overall 6, (1.22, 1.50) 5.67 < Fixed Cervical 3, (1.25, 1.64) 5.30 < Fixed rs CC vs. CT+TT Overall 2, (0.92, 1.86) Fixed Cervical 1, (0.94, 1.99) Fixed CC+CT vs. TT Overall 2, (0.44, 5.36) Random Cervical 1, (0.30, 1.86) Random CT vs. CC+TT Overall 2, (0.89, 1.26) Fixed Cervical 1, (0.85, 1.29) Fixed CC vs. TT Overall 2, (0.94, 1.99) Fixed Cervical 1, (0.98, 2.17) Fixed C vs. T Overall 5, (0.98, 1.30) Fixed Cervical 3, (0.98, 1.36) Fixed 6629 Int J Clin Exp Pathol 2016;9(7):

5 present significant association in neither overall nor cervical cancer risk (AG vs. AA+GG: overall OR = 1.04, 95% CI = , cervical OR = 1.08, 95% CI = ), Fixed-effects model or random-effects model was chosen according to Higgins I 2 test. When heterogeneity did not exist (I 2 <50%), a fixed-effects model was applied otherwise a random-effects model was used. Z values and P values were also calculated to assess the pooled ORs. IL-17 rs polymorphisms and women s cancer: As for IL-17 rs polymorphisms, 2,943 participants were analyzed in overall groups and 1,950 participants were estimated in cervical cancer subgroups (Tables 3 and 4). The meta-analysis of the overall population failed to show any significant association between IL-17 rs polymorphisms and the risk of gynecological cancers (CC vs. CT+TT: overall OR = 1.33, 95% CI = ; CC+CT vs. TT: overall OR = 1.54, 95% CI = ; CT vs. CC+TT: overall OR = 1.06, 95% CI = ; CC vs. TT: overall OR = 1.37, 95% CI = ; C vs. T: overall OR = 1.13, 95% CI = ). A subgroup analysis on cervical cancer was also performed. No significantly increased or decreased risks of cervical cancer were found for IL-17 rs polymorphisms (CC vs. CT+TT: cervical OR = 1.37, 95% CI = ; CC+CT vs. TT: cervical OR = 0.75, 95% CI = ; CT vs. CC+TT: cervical OR = 1.04, 95% CI = ; CC vs. TT: cervical OR = 1.45, 95% CI = ; C vs. T: cervical OR = 1.16, 95% CI = ). Publication bias The shapes of the funnel plots appeared to be symmetrical in all genetic comparisons, suggesting the lack of publication bias and indicating the reliability of this meta-analysis in both overall and subgroups. Discussion The inflammatory state is a necessary step to maintain and promote cancer progression and accomplish the full malignant phenotype and suppress the innate anticancer immune response. Previous researches discovered that inflammation and some cytokines accelerated the development of cancers such as cervical cancer, breast cancer and ovarian cancer [31]. Therefore, genetic mutations of these cytokines, which affect protein functions, might trigger cell transformation from autonomous proliferation to cancer growth. IL-17 is a relatively novel cytokine family, which evokes cytokine and chemokine secretion in different cell types and recruits monocytes and neutrophils into the microenvironment of inflammation [32]. IL-17A rs polymorphisms and IL-17F rs polymorphisms were among the most widely investigated SNPs in IL-17. Several molecular epidemiological studies have assessed the association between IL-17 gene polymorphisms and cancer risk, including non-small cell lung cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma, and breast cancer [33, 34]. One meta-analysis reported that IL-17A rs G/A polymorphism was associated with elevated gastric cancer risk. However, whether these polymorphisms play a role in women s cancer still remains to be solved. In order to better understand the role of rs and rs polymorphisms in women s cancer risk, and to draw a more concrete conclusion, the current meta-anal ysis was performed. In the present meta-analysis, 9 case-control studies were enrolled. 5 were about rs polymorphisms and 4 were about rs polymorphisms. As for rs polymorphisms, 3,084 participants were analyzed for overall cancer risk and 1,962 participants were calculated for cervical cancer risk. Significant association was found between IL-17 rs polymorphisms and the risk of overall cancer types in 4 different genotype or allele comparisons. Heterozygous mutants alone failed to present any significant association, indicating that allele A might increase the risk of women s cancer development. Among the 4 case-control studies of rs polymorphisms, 2,943 participants were analyzed in overall groups and 1,950 participants were estimated in cervical cancer subgroups. 3 studies reported that neither allele C nor T conferred higher risk for cervical cancer. 1 study reported that IL-17 SNP C allele had no impact on breast cancer risk. By performing a metaanalysis, we concluded that IL-17 rs polymorphisms and the risk of women s cancer were not significantly associated. The pooled results of a subgroup analysis on cervical cancer were consistent with the overall meta-analysis. Since there were no case-control studies 6630 Int J Clin Exp Pathol 2016;9(7):

6 available on other types of women s cancer like endometrial cancer and vulvar cancer, we could hardly make any conclusion on whether IL-17 gene variants could affect the development on these cancers. Despite our efforts to pool the results of currently published articles, some disadvantages of the present meta-analysis should not be ignored. Firstly, the number of enrolled studies was very limited. 5 studies were found for rs polymorphisms and 4 were for rs polymorphisms. As for cancer types, only 3 articles about cervical cancer, 1 article about breast cancer and 1 article about ovarian cancer. It is possible that the results of further investigations and studies on other types of women s cancer might be different from the present conclusion, thus cautions should be paid to explain the results. Secondly, this metaanalysis was based on unadjusted estimations. It is known that other risk factors like primiparity age and menopausal status were also important in the development of women s cancer [35]. These confounding factors might affect the validity of the results. Thirdly, available studies regarding these associations in Chinese people were not sufficient. Included articles analyzed mainly Chinese Han people. Even though Han ethnicity composes the majority of Chinese, other ethnic minorities should not be ignored. Thus, studies enrolling diverse ethnics were required. To our knowledge, the present study was the first meta-analysis exploring the association between IL-17 polymorphism and the risks of women s cancer. Despite all the disadvantages mentioned above, we could still conclude that IL-17 rs instead of rs polymorphisms were associated with the risks of women s cancer in Chinese people. Further studies are needed to validate the conclusion. Acknowledgements This work was supported by the National High Technology Research and Development Program of China (No. 2014AA020708). Disclosure of conflict of interest None. Address correspondence to: Xia Zhao, Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu , Sichuan, PR China. Tel: ; Fax: ; drzhaoxia@163.com; xia-zhao@126.com References [1] Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA. Osteoclast differentiation factor RANKL controls development of progestindriven mammary cancer. Nature 2010; 468: [2] Balbi G, Napolitano A, Giordano F, Capuano S, Manganaro MA, Di Martino L, Fusco D, Grauso F, Seguino E. Role of the association of highrisk HPV identified by real-time PCR in cervical preneoplastic lesions. Eur J Gynaecol Oncol 2012; 33: [3] Ruiz de Gauna B, Rodriguez D, Olartecoechea B, Aubá M, Jurado M, Gómez Roig MD, Alcázar JL. Diagnostic performance of IOTA simple rules for adnexal masses classification: a comparison between two centers with different ovarian cancer prevalence. Eur J Obstet Gynecol Reprod Biol 2015; 191: [4] International Agency for Research on Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in cancer.aspx. [5] Sopik V, Rosen B, Giannakeas V, Narod SA. Why have ovarian cancer mortality rates declined? Part III. Prospects for the future. Gynecol Oncol 2015; 138: [6] Shi WJ, Liu H, Wu D, Tang ZH, Shen YC, Guo L. Stratification analysis and case-control study of relationships between interleukin-6 gene polymorphisms and cervical cancer risk in a Chinese population. Asian Pac J Cancer Prev 2014; 15: [7] Chen X, Han S, Wang S. Interactions of IL-12A and IL-12B polymorphisms on the risk of cervical cancer in Chinese women. Clin Cancer Res 2009; 15: [8] Chagas BS, Gurgel AP, da Cruz HL. An interleukin-10 gene polymorphism associated with the development of cervical lesions in women infected with human papillomavirus and using oral contraceptives. Infect Genet Evol 2013; 19: [9] Yang YC, Chang TY, Chen TC, Chang SC, Lin WS, Lee YJ. Genetic variants in interleukin-18 gene and risk for cervical squamous cell carcinoma. Hum Immunol 2013; 74: [10] Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity 2004; 21: Int J Clin Exp Pathol 2016;9(7):

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