Int J Clin Exp Med 2015;8(9):15857-15861 www.ijcem.com /ISSN:1940-5901/IJCEM0010983 Original Article Survivin -31 G/C polymorphism might contribute to colorectal cancer (CRC) risk: a meta-analysis Linhua Yao, Yi Hu, Zhongmin Deng, Jingjing Li Department of Gastroenterology, The First Affiliated Hospital of Huzhou Teachers College, 158 Guang Chuang Hou Lu, Huzhou 313000, Zhejiang, China Received June 2, 2015; Accepted July 21, 2015; Epub September 15, 2015; Published September 30, 2015 Abstract: Published data has shown inconsistent findings about the association of survivin -31 G/C polymorphism with the risk of colorectal cancer (CRC). This meta-analysis quantitatively assesses the results from published studies to provide a more precise estimate of the association between survivin -31 G/C polymorphism as a possible predictor of the risk of CRC. We conducted a literature search in the PubMed, Web of Science, and Cochrane Library databases. Stata 12 software was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs) based on the available data from each article. Six studies including 1840 cases with CRC and 1804 controls were included in this study. Survivin -31 G/C polymorphism was associated with a significantly increased risk of CRC (OR = 1.78; 95% CI, 1.53-2.07; I2 = 0%). In the race subgroup analysis, both Asians (OR = 1.72; 95% CI, 1.44-2.05; I2 = 0%) and Caucasians (OR = 1.93; 95% CI, 1.46-2.55; I2 = 0%) with survivin -31 G/C polymorphism had increased CRC risk. In the subgroup analysis according to site of CRC, survivin -31 G/C polymorphism was not associated with colon cancer risk (OR = 2.02; 95% CI, 0.79-5.22; I2 = 82%). However, this polymorphism was significantly associated with rectum cancer risk (OR = 1.98; 95% CI, 1.42-2.74; I2 = 0%). In the subgroup analysis by clinical stage, both early stage (I+II) and advanced stage (III+IV) were associated with survivin -31 G/C polymorphism (OR = 1.61; 95% CI, 1.20-2.16; I2 = 0% and OR = 2.30; 95% CI, 1.70-3.13; I2 = 0%, respectively). In the subgroup analysis by smoke status, both smokers and non-smokers with survivin -31 G/C polymorphism showed increased CRC risk (OR = 1.47; 95% CI, 1.01-2.13; I2 = 60% and OR = 1.71; 95% CI, 1.28-2.30; I2 = 0%, respectively). In the subgroup analysis by drink status, both drinkers and non-drinkers with survivin -31 G/C polymorphism showed increased CRC risk (OR = 1.58; 95% CI, 1.06-2.37; I2 = 8% and OR = 1.61; 95% CI, 1.23-2.11; I2 = 0%, respectively). In conclusion, this metaanalysis suggested that survivin -31 G/C polymorphism may be associated with the risk of CRC Keywords: Colorectal cancer, survivin, meta-analysis, polymorphism Introduction Colorectal cancer (CRC) is one of the most common malignancies and represents a significant cause of morbidity and mortality worldwide [1]. Recent progress in diagnosis and therapy has helped to save the lives of many patients at early stages of this malignancy, but the prognosis for patients with advanced disease or metastasis is still poor. Therefore, further investigation into the molecular pathogenesis of CRC and the consequential development of novel targeted therapeutics are needed. Survivin is a small protein and tumor associated antigen expressed in many cancers. Survivin normally functions as an apoptosis inhibitor, via spindle microtubule and mitotic checkpoint regulation [2]. It is a potential target for immunotherapy since it is highly expressed in many cancers [3], it is linked to worse prognosis in both solid and hematologic tumors, and it is undetectable in almost all normal adult tissues [4]. Published data has shown inconsistent findings about the association of survivin -31 G/C polymorphism with the risk of CRC [5-10]. This meta-analysis quantitatively assesses the results from published studies to provide a more precise estimate of the association between survivin -31 G/C polymorphism as a possible predictor of the risk of CRC. Methods Publication search We conducted a literature search for relevant studies on the relationships between survivin -31 G/C polymorphism and CRC risk in the PubMed, Web of Science, and Cochrane Library Survivin and CRC Quality assessment Figure 1. Flow of study identification, inclusion, and exclusion. databases (up to May 15, 2015). The following search terms were used: “survivin”; and “Colorectal cancer”, and “CRC”. The searched studies were limited to the English and Chinese. Inclusion and exclusion criteria All the studies identified were reviewed independently by two investigators and the studies were included if they fulfilled the following criteria: (1) a case-control study or cohort study was reported; (2) the cases were diagnosed as CRC and the control group was composed of healthy individuals; (3) the genotypes of survivin -31 G/C polymorphism were described in the studies. The references were excluded from the meta-analysis as follows: (1) the study was not related to CRC; (2) the reference did not describe genotypes of the survivin -31 G/C polymorphism in the two groups; (3) the reference consisted of duplicate data or publications from the included studies. Data extraction The following data were recorded from each article: first author, years of publication, ethnicity, gender, age, numbers of subjects, site of CRC, stage of CRC, smoke and drink status. The data were extracted by two of the authors independently. Discrepancies between these two authors were resolved by discussion. 15858 Quality assessment was conducted for each article according to Strengthening the Reporting of Genetic Association studies (STREGA) [11] containing eleven items associated with valid data reported in the study. For each item, there are three degrees, “yes” (scored 2), “can’t tell” (scored 1) or “no” (scored 0), after evaluating each item, a total score from 0 to 22 was reported for each article. Studies would be divided into 3 grades: Grade A (scored 1522, high quality), Grade B (scored 8-14, medium quality), or Grade C (scored 0-7, inferior quality). Only the studies of Grade A or B would be included in the final analysis. Statistical analysis Stata 12 software was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs) based on the available data from each article. P < 0.05 was considered statistically significant. The recessive model was estimated. Cochran’s Q-statistic and the I2 test were used to test the heterogeneity among the included studies, and P < 0.1 and I2 > 50% suggested significant differences in study heterogeneity. When significant heterogeneity was observed across studies, the pooled results were based on random effects models. The χ2 test was applied to assess whether the genotype distributions of the control populations conformed to Hardy-Weinberg equilibrium (HWE), and P < 0.05 was considered statistically significant. Begg’s funnel plot and Egger’s test were used to detect publication bias. Results Study characteristics In our study, we initially searched 54 related references, among which 12 were duplicates. When removing the duplicates and other unrelated references, 6 references met our inclusion criteria and were recruited in the metaInt J Clin Exp Med 2015;8(9):15857-15861 Survivin and CRC Table 1. Characteristics of the studies included in this meta-analysis Age (years) Gender of case No. of No. of Site of Stage Smoke Drink case control disease status status status Study Year Ethnicity Gazouli 2009 Caucasian 33-93 158 men/154 women Huang 2010 Asian NA Quality grade HardyWeinberg equilibrium 312 362 NA Yes NA NA A (scored 21) Yes 435 men/267 women 702 711 NA NA Yes Yes A (scored 20) Yes Antonacopoulou 2011 Caucasian 56-86 NA 163 132 NA NA NA NA A (scored 18) Yes Duan 2012 Asian NA 114 men/92 women 206 129 Yes NA NA NA A (scored 19) Yes Liu 2012 Asian 25-84 95 men/87 women 182 200 NA NA Yes Yes A (scored 17) Yes Li 2013 Asian NA 152 men/123 women 275 270 Yes Yes NA NA A (scored 19) Yes NA, not available. Table 2. Results of this meta-analysis Overall Ethnicity Caucasian Asian Cancer type Rectum Colon Stage I+II III+IV Smoking Yes No Drinking Yes No Test of association OR (95% CI) P Value 1.78 (1.53-2.07) <0.00001 Heterogeneity I2 (%) P Value 0 0.68 1.93 (1.46-2.55) <0.00001 1.72 (1.44-2.05) <0.00001 0 0 0.32 0.65 1.98 (1.42-2.74) 2.02 (0.79-5.22) <0.0001 0.14 0 82 0.87 0.02 1.61 (1.20-2.16) 0.001 2.30 (1.70-3.13) <0.00001 0 0 0.54 0.48 1.47 (1.01-2.13) 1.71 (1.28-2.30) 0.04 0.0003 60 0 0.12 0.96 1.58 (1.06-2.37) 1.61 (1.23-2.11) 0.03 0.0005 8 0 0.30 0.75 analysis (Figure 1). The information of the included studies were listed in Table 1. There were 2644 subjects, including 1840 cases with CRC and 1804 controls. All studies received a score of more than or equal to 17, indicating good quality. Results of meta-analysis The results of the association between survivin -31 G/C polymorphism and CRC risk are summarized in Table 2. Survivin -31 G/C polymorphism was associated with a significantly increased risk of CRC (OR = 1.78; 95% CI, 1.532.07; I2 = 0%; Figure 2). In the race subgroup analysis, both Asians (OR = 1.72; 95% CI, 1.442.05; I2 = 0%) and Caucasians (OR = 1.93; 95% CI, 1.46-2.55; I2 = 0%) with survivin -31 G/C polymorphism had increased CRC risk. In the 15859 subgroup analysis according to site of CRC, survivin -31 G/C polymorphism was not associated with colon cancer risk (OR = 2.02; 95% CI, 0.79-5.22; I2 = 82%). However, this polymorphism was significantly associated with rectum cancer risk (OR = 1.98; 95% CI, 1.42-2.74; I2 = 0%). In the subgroup analysis by clinical stage, both early stage (I+II) and advanced stage (III+IV) were associated with survivin -31 G/C polymorphism (OR = 1.61; 95% CI, 1.20-2.16; I2 = 0% and OR = 2.30; 95% CI, 1.70-3.13; I2 = 0%, respectively). In the subgroup analysis by smoke status, both smokers and non-smokers with survivin -31 G/C polymorphism showed increased CRC risk (OR = 1.47; 95% CI, 1.01-2.13; I2 = 60% and OR = 1.71; 95% CI, 1.28-2.30; I2 = 0%, respectively). In the subgroup analysis by drink status, both drinkers and non-drinkers with survivin -31 G/C polymorphism showed increased CRC risk (OR = 1.58; 95% CI, 1.06-2.37; I2 = 8% and OR = 1.61; 95% CI, 1.23-2.11; I2 = 0%, respectively). Figure 3 showed the Egger’s publication bias plot in the meta-analysis. The plots shape, as well as the P value from Egger’s regression (P = 0.655), did not show evidence of publication bias. Discussion In this meta-analysis, we investigated the association between the survivin -31 G/C polymorphism and CRC risk including 1840 cases with CRC and 1804 controls. We found that individuals with survivin -31 G/C polymorphism showed an increased risk of CRC in the overall population. In the stratified analysis by ethnicity, the significant association was observed in Asians Int J Clin Exp Med 2015;8(9):15857-15861 Survivin and CRC Figure 2. Meta-analysis for the association between survivin -31 G/C polymorphism and CRC risk. as strong independent prognostic factors, with high hazard ratios, for survival and tumor recurrence in colon cancer patients [13]. A recent meta-analysis revealed a positive correlation between survivin expression and poor prognosis in CRC [14]. In addition, that meta-analysis revealed a significant association between expression of survivin and the presence of lymph node metastases or blood vessel invasion [14]. Functionally, survivin exhibits distinct functions during cell cycle progression or as inhibitor of programmed cell death together with IAP-family member XIAP, by promoting stability of XIAP and synergistically inhibition of caspase-9 [15]. In addition, survivin promotes by complexing XIAP invasion and migration of malignant cells via NF-κB pathways, apparently contributing to metastasis [16]. Surviving also contributed to other cancers. Javid et al. demonstrated that survivin (-31G > C) was associated with significantly increased survivin gene expression and ultimately may contribute in Figure 3. Funnel plot for the association between survivin -31 G/C polymorthe poor clinical outcome of phism and CRC risk. non-small cell lung cancer patients [17]. Aminimoghadand Caucasians. In the stratified analysis by dam et al. observed survivin rs9904341C allele site of CRC, survivin -31 G/C polymorphism sigwas associated with increased endometrial nificantly increased rectum cancer risk, but not carcinoma risk [18]. Chen and colleagues sugcolon cancer risk. We found significant heterogest that the high survivin expression was geneity in colon cancer risk. Thus, more studies associated with tumor stage and grade and with colon cancer risk are still needed. In the may present a predictive marker of overall sursubgroup analysis by stage of CRC, smoking vival in urothelial carcinoma [19]. status and drink status, positive results were Some limitations should be addressed. First, found in all these subgroup analyses. only published English and Chinese language Kim et al. found that survivin was a candidate studies were included in this meta-analysis, so biomarker for the prediction of recurrence and the language bias might influence the results. survival in CRC [12]. Goossens-Beumer et al. Second, the sample sizes in several of the also suggested that identified combined incorporated studies were relatively small, expression levels of Aldh1, Survivin, and EpCAM which may reduce the strength of our conclu15860 Int J Clin Exp Med 2015;8(9):15857-15861 Survivin and CRC sions. In addition, our result was on the basis of unadjusted estimates, while a more accurate analysis should be carried out if more detailed individual information was available, which would allow for an adjusted estimate by other causes such as age and sex. In conclusion, this meta-analysis suggested that survivin -31 G/C polymorphism may be associated with the risk of CRC. [8] [9] [10] Acknowledgements This work was supported by Medicine and health science and technology plan projects in zhejiang province (2012KYB200) and Huzhou city technology bureau project (2012 ysb15). [11] Disclosure of conflict of interest None. Address correspondence to: Linhua Yao, Department of Gastroenterology, The First Affiliated Hospital of Huzhou Teachers College, 158 Guang Chuang Hou Lu, Huzhou 313000, Zhejiang, China. Tel: 86-0572-2039425; E-mail: linhuayao11@126. com [12] [13] References [1] [2] [3] [4] [5] [6] [7] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90. Ambrosini G, Adida C, Altieri DC. A novel antiapoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997; 3: 917-21. Kawasaki H, Altieri DC, Lu CD, Toyoda M, Tenjo T, Tanigawa N. Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res 1998; 58: 5071-4. Stauber RH, Mann W, Knauer SK. Nuclear and cytoplasmic survivin: molecular mechanism, prognostic, and therapeutic potential. Cancer Res 2007; 67: 5999-6002. Gazouli M, Tzanakis N, Rallis G, Theodoropoulos G, Papaconstantinou I, Kostakis A, Anagnou NP, Nikiteas N. Survivin -31G/C promoter polymorphism and sporadic colorectal cancer. Int J Colorectal Dis 2009; 24: 145-50. Huang J, Wang J, Wang L, Liu H, Wei Y, Huang M. Associationbetween Survivin Promoter -31C/G Polymorphism and Genetic Susceptibility to Sporadic Colorectal Cancer. J SUN Yatsen Univ (Med Sci) 2010; 31: 59-63. Antonacopoulou AG, Floratou K, Bravou V, Kottorou A, Dimitrakopoulos FI, Marousi S, Stavropoulos M, Koutras AK, Scopa CD, Kalofonos HP. The survivin -31 snp in human colorectal cancer correlates with survivin 15861 [14] [15] [16] [17] [18] [19] splice variant expression and improved overall survival. Cell Oncol (Dordr) 2011; 34: 381-91. Duan F. The Study on the Relationship between Survivin promoter SNP and the Colorectal Cancer. Master’s thesis. Lu Zhou Medical College 2012. Liu Y. The Association of Survivin Polymorphism with the Risk of Colorectal Cancer. Master’s thesis. Hebei Medical College 2012. Li XB, Li SN, Yang ZH, Cao L, Duan FL, Sun XW. Polymorphisms of survivinand its protein expression are associated with colorectal cancersusceptibility in Chinese population. DNA Cell Biol 2013; 32: 236-42. Little J, Bradley L, Bray MS, Clyne M, Dorman J, Ellsworth DL, Hanson J, Khoury M, Lau J, O’Brien TR, Rothman N, Stroup D, Taioli E, Thomas D, Vainio H, Wacholder S, Weinberg C. Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations. Am J Epidemiol 2002; 156: 300-10. Kim ST, Sohn I, DO IG, Jang J, Kim SH, Jung IH, Park JO, Park YS, Talasaz A, Lee J, Kim HC. Transcriptome analysis of CD133-positive stem cells and prognostic value of survivin in colorectal cancer. Cancer Genomics Proteomics 2014; 11: 259-66. Goossens-Beumer IJ, Zeestraten EC, Benard A, Christen T, Reimers MS, Keijzer R, Sier CF, Liefers GJ, Morreau H, Putter H, Vahrmeijer AL, van de Velde CJ, Kuppen PJ. Clinical prognostic value of combined analysis of Aldh1, Survivin, and EpCAM expression in colorectal cancer. Br J Cancer 2014; 110: 2935-44. Krieg A, Werner TA, Verde PE, Stoecklein NH, Knoefel WT. Prognostic and clinicopathological significance of survivin in colorectal cancer: a meta-analysis. PLoS One 2013; 8: e65338. Dohi T, Okada K, Xia F, Wilford CE, Samuel T, Welsh K, Marusawa H, Zou H, Armstrong R, Matsuzawa S, Salvesen GS, Reed JC, Altieri DC. An IAP-IAP complex inhibits apoptosis. J Biol Chem 2004; 279: 34087-90. Mehrotra S, Languino LR, Raskett CM, Mercurio AM, Dohi T, Altieri DC. IAP regulation of metastasis. Cancer Cell 2010; 17: 53-64. Javid J, Mir R, Julka PK, Ray PC, Saxena A. Role of survivin re-expression in the development and progression of non-small cell lung cancer. Tumour Biol 2015; 36: 5543-50. Aminimoghaddam S, Shahrabi-Farahani M, Mohajeri-Tehrani M, Amiri P, Fereidooni F, Larijani B, Shafiee G, Amoli MM. Epistatic interaction between adiponectin and survivin gene polymorphisms in endometrial carcinoma. Pathol Res Pract 2015; 211: 293-7. Chen HA, Su CM, Hsieh HY, Tung CL, Hsu CD, Wang YH, Shen CH. Clinical significance of survivin expression in patients with urothelial carcinoma. Dis Markers 2014; 2014: 57498. Int J Clin Exp Med 2015;8(9):15857-15861