REVIEW A Systematic Review and Meta-Analysis of Three Gene Variants Association with Risk of Prostate Cancer: An Update Yu Chen, Huan Zhong, Jian-Guo Gao, Jian-Er Tang, Rongjiang Wang* Purpose: Prostate cancer (PCa) is one of the most commonly diagnosed male malignancies. Nu- merous studies have investigated the role of genetic variants in PCa risk. However, the results re- main unclear. The purpose of this study was to evaluate the relationship between single-nucleo- tide polymorphism (SNP) rs2228001 in xeroderma pigmentosum group C (XPC), SNP rs4073 in interleukin 8 (IL8), and SNP rs2279744 in mouse double minute 2 (MDM2) homolog gene with PCa susceptibility. Materials and Methods: Electronic database of PubMed, Medline, and Embase were searched for eligible articles published between January 2000 and April 2014. The odd ra- tio (OR) with its 95% confidence interval (CI) were calculated to estimate the strength of association. Results: A total 18 case-control studies, including 5725 PCa cases and 5900 healthy controls, were screened out. Six studies were eligible for each SNP. For XPC 939A/C polymorphism, no significant association was found with PCa risk in the whole population (P > .05). No relationship in subgroup analysis was found by ethnicity. For IL8 -251T/A variant, the A allele was not related with PCa risk in any genetic models when compared with those individuals without A allele. For MDM2 -309T/G mutation, the G allele was not as- sociated with the increased risk of PCa in total population and subgroup analysis by ethnicity as well. Conclusion: Our study demonstrated that all these three genetic polymorphisms were not associated with an in- creased risk of developing PCa, which might also provide an insight into the future research. Further large-scale studies with concerning the gene-gene and gene-environment interactions are needed to elucidate final conclusion. Keywords: prostatic neoplasms; genetics; risk factors; gene expression regulation; humans; tumor marker; biological. INTRODUCTION Prostate cancer (PCa) is the common malignan-cies among men in the world. It is also the sec- ond and third cause of cancer-related death in the USA and Europe, respectively.(1,2) Every year, a total of 238,590 new cases are emerging and 29,720 death are occurring according to cancer statistics, 2013.(3) Multiple risk factors such as hormones, family history and lifestyle are associated with PCa. Due to extreme heterogeneity in PCa incidences worldwide, major determining factors have not been detected yet,(4) and the pathogenesis mechanism is still unclear. Further- more, the prevention and treatment of PCa remain complicated for treatment options depending on dis- ease stage and patient choice.(5) Thus, there is an ur- gent need to explore the molecular mechanism under- lying this disease and develop novel target therapies. During the last two decades, genetic factors are con- sidered to contribute substantially in the development of PCa. For example, increased B-cell lymphoma 2 (Bcl-2) expression was associated with lower biochem- ical-free survival in patients with advanced PCa.(6) Pol- ymorphisms of drug-metabolizing genes cytochrome P4501A1 (CYPlAl)(7) and prostate-specific antigen (PSA)(8) genes were shown to be related with increase the risk of sporadic PCa, and they might be predispos- Department of Urology, Affiliated Hospital of Huzhou Teachers› College, The First People›s Hospital of Hu zhou, Hu zhou, 313000, China. *Correspondence: Department of Urology, Affiliated Hospital of Huzhou Teachers› College, The First People›s Hospital of Huzhou, Huzhou, 313000, China. Tel: +86 572 2575091. Fax: +86 572 2023728. E-mail: rongjiangwang_r@163.com. Received November 2014 & Accepted May 2015 ing factors for PCa. Several genes were shown to be involved in the pathogenicity of PCa. The xeroder- ma pigmentosum group C (XPC) gene is located on chromosome 3p25 and is a 940-residue DNA binding protein. It serves as the primary initiating factor in the global genome nucleotide excision repair (GG-NER) in human, and plays a vital role in the early steps, es- pecially in damage recognition, open complex for- mation and reparation.(9) Recent reports suggest that XPC also stimulates repair of oxidative lesions by NER. In cells, XPC binds to human homolog of re- ticulum-associated degradation B (Rad) 23 (hHR23B) to form the XPC-hHR23B complex,(10) which is in- volved in the DNA damage recognition and DNA re- pair initiation in the NER pathway, and is necessary to support NER activity in vitro.(11) Sequence variants of the XPC gene may alter NER capacity and modu- late cancer risk. One single-nucleotide polymorphism (SNP) Lys939Gln (an A to C substitution) in exon 15 of XPC has been identified and is the most studied. Interleukin-8 (IL8) gene, located on chromosome 4q12- 21 in humans, is composed of four exons, three introns, and a proximal promoter region. It is an important member of CXC chemokine family(12) and is produced by a wide range of normal cells to initiate and amplify acute inflammatory reactions.(13) IL8 is well known for its leukocyte chemotactic properties. Many studies have Review 2138 demonstrated that IL8 may play a vital role in tumori- genesis, including angiogenesis, adhesion, invasion and metastasis.(14) In the promoter region of the IL8 gene- 251 base pairs upstream of the transcriptional start sit, a T/A SNP has been identified, and studies have shown that it influences the production of IL8 and af- fects the transcriptional activity of the IL8 promoter.(15) Mouse double-minute 2 (MDM2) is an E3-ubiquitin ligase which could bind to p53 with high affinity. It in- hibits and promotes the degradation of the tumor sup- pressor protein, p53.(16,17) Overexpression of MDM2 is associated with tumor proliferation, and an early onset of tumorigenesis.(18) Studies have demonstrated that a mutation in the promoter region of the MDM2 gene (-309 T/G; SNP309) could result in increasing the ex- pression of MDM2, leading to the attenuation of p53.(19) Although independent study has identified the associ- ation between these polymorphisms and PCa risk, the results remained inconsistent rather than conclusive. Hirata and colleagues showed that XPC Lys939Gln polymorphism might be a risk factor for PCa in Jap- anese population;(20) however, Liu and colleagues did not found a significant association between this poly- morphism and PCa in Chinese population.(21) McCar- ron and colleagues firstly demonstrated that IL8 var- iant might have a significant effect on development of PCa;(22) whereas Michaud and colleagues identified that IL8 variant did not play a role in the risk of PCa. (23) Xu and colleagues suggested that MDM2 309G al- lele is significantly related with PCa risk;(24) while Jerry and colleagues found no association between MDM2 SNP 309 and disease recurrence risk, clinicopatho- logic variables and overall survival outcome in PCa. (25) Therefore, the objective of this study was to sys- tematically evaluate the prevalence of the above men- tioned genetic polymorphisms in patients diagnosed with PCa, and comprehensive and reliable assessment of correlations of these polymorphisms with PCa risk. MATERIALS AND METHODS Identification and Eligibility of Relevant Studies We conducted a comprehensive literature search using the electronic database of PubMed, Medline, and Em- base for relevant articles published between January 2000 and April 2014. The following terms «prostate cancer or prostatic cancer», «xeroderma pigmentosum complementation group C or XPC», «interleukin-8 or IL8», «murine double minute 2 or MDM2», and «polymorphisms or variants or mutations» as well as their combinations were used to retrieve the re- lated articles. References of retrieved articles were restricted with English language. Our research fo- Table 1. Characteristics of the included studies in the meta-analysis. First Author Year Country Ethnicity Cases No. Control No. Genotyping Method XPC 939A/C Hirata27 2007 Japan Asian 165 165 PCR-RFLP Agalloi32 2010 USA Caucasians 1308 1266 PCR-RFLP Agalloi32 2010 USA African-Americans 149 85 PCR Liu21 2012 China Asian 202 221 PCR-RFLP Mittal28 2012 India Caucasians 195 250 PCR Sorour29 2013 Egypt African 50 50 PCR-RFLP Zhang30 2014 China Asian 229 238 PCR, MALDI-TOF MS IL8 -251T /A McCarron22 2002 UK Caucasians 247 263 PCR Michaud23 2006 USA Caucasians 503 652 Taqman-PCR Yang38 2006 Finland Caucasians 520 418 Taqman Wang37 2009 USA Caucasians 254 252 Taqman Zhang35 2010 USA Caucasians 193 197 PCR Dluzeniewski36 2012 USA Caucasians 484 484 Taqman-PCR MDM2 -309T/G Kibei44 2008 USA Caucasians 186 222 Pyrosequencing Stoehr43 2008 Germany Caucasians 145 124 PCR-RFLP Hirata39 2009 Japan Asian 140 167 PCR-RFLP XuB42 2010 China Asian 209 268 PCR-RFLP Knappskog41 2012 Norway Caucasians 666 675 PCR Manda40 2012 Indian Caucasians 192 224 PCR-RFLP Abbreviations: PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; MALDI-TOF MS, matrix-assisted laser desorption ionisation mass spectrometry – time of flight. Association of Three Gene Variants with Risk of PCa-Chen et al. Vol 12 No 03 May-June 2015 2139 cused on studies that had been conducted in human. Criteria for Inclusion The included studies must meet the following criteria: 1) the paper should be case-control or cohort associa- tion studies; 2) PCa cases were diagnosed and histo- pathologically confirmed; 3) controls were cancer free, unrelated, age- and sex-matched healthy individuals of similar ethnicity; 4) each study included at least one of the three polymorphisms, rs2228001 in XPC (939A/C), rs4073 in IL8 (-251T/A), and rs2279744 in MDM2 (-309T/G); 5) genotype distribution information in cases and controls were available to extract, and 5) genotype distribution of control for a certain polymor- phism must be in Hardy-Weinberg equilibrium (HWE). Data Extraction Two investigators independently assessed the quality of the included studies according to the data extract- ed from each study. Any disagreement was solved by consulting with a third author. The following infor- mation was extracted from each article: first author, year of publication, country, ethnicity, total numbers, and genotype distributions in PCa cases and controls. Statistical Analysis The overall association between genetic polymorphisms and PCa risk was measured by odds ratio (OR) and its 95% confidence interval (CI). The Z test was employed to determine the significance of the pooled ORs with a P value less than .05 considered statistically significant. The allelic model (C vs. A for XPC 939A/C; A vs. T for IL8-251A/T; G vs. T for MDM2 -309T/G) and genotype genetic models (co-dominant effects: CC vs. AA XPC 939A/C; AA vs. TT IL8 -251A/T; GG vs. TT MDM2- 309T/G; dominant effect: CC+AC vs. AAXPC 939A/C; Table 2. Distribution of genotypes and alleles in the individual studies. First Author Cases Controls XPC AA AC CC A C AA AC CC A C Hirata27 77 78 10 232 98 72 70 23 214 116 Agalloi32 457 595 205 1509 1005 461 600 190 1522 980 Agalloi32 70 61 16 201 93 36 38 9 110 56 Liu21 86 85 31 257 147 102 100 19 304 138 Mittal28 94 73 28 261 129 127 104 19 358 142 Sorour29 16 25 9 57 43 18 27 5 63 37 Zhang30 58 38 33 354 104 170 37 31 377 99 IL8 AA AT TT A T AA AT TT A T McCarron22 59 122 57 240 236 54 105 76 213 257 Michaud23 112 225 147 449 519 151 310 152 612 614 Yang38 103 236 181 442 598 66 217 135 349 487 Wang37 69 127 58 265 243 62 138 52 262 242 Zhang35 60 102 80 93 Dluzeniewski36 107 218 121 432 460 106 207 133 419 473 MDM2 TT GT GG T G TT GT GG T G Kibei44 85 88 13 258 114 90 98 32 278 162 Stoehr43 61 66 18 188 102 41 64 19 146 102 Hirata39 58 56 26 172 108 56 79 32 191 143 Xu B42 44 118 47 206 212 68 143 57 279 257 Knappskog41 297 277 92 871 461 305 295 75 905 445 Manda40 67 71 54 205 179 53 98 73 204 244 Figure 1. Flow chart diagram of literature review. Association of Three Gene Variants with Risk of PCa-Chen et al. Review 2140 AA+AT vs. TT IL8 -251A/T; GG+GT vs. TT MDM2 -309T/G; and recessive effect: CC vs. AC+AA XPC 939A/C; AA vs. AT+TT IL8 -251A/T; GG vs. GT+TT MDM2 -309T/G) were examined. The I2 test and the Q test were used to assess the between-study heterogenei- ty. The fixed-effects model is used when the effects are assumed to be homogenous (less than 50% for the I2 test and P value more than .01 for the Q test), while the random effects model is used when they are heterogene- ous. The evidence of publication bias was assessed by visual funnel plot inspection. Statistical analyses were conducted using Review Manager (RevMan) software (version 5.2, The Cochrane Collaboration, Oxford, UK), and followed the program described by Collab- oration and colleagues.(26) All the tests were two-sided. RESULTS Study Selection and Characteristics The electronic database search identified 323 references. After applying the inclusion criteria, 32 full-text articles comprehensively assessed against inclusion criteria. Removing duplicate documents, 18 articles were ulti- mately included in the systematic review and meta-anal- ysis. The study selection process is shown in Figure 1. For XPC 939A/C, 6 studies(27-32) consisted three ethnici- ty (Asian, Caucasians and African) reporting 2245 cas- es and 2258 controls were selected. Among them, the research conducted by Agalliu and colleagues(32) con- sisted two ethnicities. For IL8 -251T/A, 6 studies(33-38) included 1942 cases and 1964 controls were enrolled, all of which had Caucasians ethnicity. For MDM2 -309T/G, 6 studies(39-44) contained 1538 cases and 1678 controls including Asian and Caucasians ethnicities were selected. The main characteristics of the included studies are listed in Table 1. The distributions of geno- types in the individual studies are presented in Table 2. Association between XPC 939A/C Variant and PCa Risk The results of allele and genotypes of XPC polymor- phism in this meta-analysis are shown in Table 3. The heterogeneity between studies was calculated, and the Table 3. Meta-analysis of xeroderma pigmentosum group C 939A/C polymorphism in prostate cancer. Variables Comparison No. OR (95% CI) P Value* Z Ph** I2 (%) Model Overall C vs. A 7 1.06 (0.97-1.15) .22 1.22 0.29 18 F CC vs. AA 7 1.19 (0.85-1.68) .32 1.00 0.04 54 R CC + AC vs. AA 7 1.03 (0.92-1.17) .59 0.54 0.94 0 F CC vs. AC + AA 7 1.20 (0.85-1.70) .30 1.04 0.03 58 R Asian C vs. A 3 1.04 (0.79-0.37) .78 0.28 0.09 59 R CC vs. AA 3 1.00 (0.45-2.22) .99 0.01 0.01 77 R CC + AC vs. AA 3 1.06 (0.84-1.34) .62 0.49 0.62 0.0 F CC vs. AC + AA 3 0.99 (0.44-2.21) .97 0.03 0.007 80 R Caucasians C vs. A 2 1.06 (0.95-1.18) .27 1.09 0.24 29 F CC vs. AA 2 1.36 (0.77-2.42) .29 1.06 0.08 67 R CC + AC vs. AA 2 1.03 (0.89-1.20) .65 0.45 0.69 0.0 F CC vs. AC + AA 2 1.39 (0.76-2.53) .28 1.08 0.06 72 R African C vs. A 2 1.02 (0.74-1.42) .90 0.13 0.33 0.0 F CC vs. AA 2 1.20 (0.57-2.52) .63 0.48 0.32 0.0 F CC+AC vs. AA 2 0.94 (0.60-1.47) .77 0.29 0.49 0.0 F CC vs. AC + AA 2 1.28 (0.64-2.57) .48 0.70 0.36 0.0 F Abbreviations: OR, odds ratio; CI, confidence interval. No, number of included studies. * P value for overall effect. ** P value for heterogeneity among studies. Comparison No. OR (95% Cl) P Value* Z Ph** I2 (%) Model A vs. T 5 1.01 (0.92-1.10) .88 0.15 0.23 29 F AA vs. TT 5 1.03 (0.86-1.23) .75 0.32 0.25 26 F AA + AT vs. TT 5 0.99 (0.79-1.24) .90 0.12 0.04 59 R AA vs. AT + TT 6 1.02 (0.88-1.17) .80 0.25 0.27 21 F Abbreviations: OR, odds ratio; CI, confidence interval. No, number of included studies. * P value for overall effect. ** P value for heterogeneity among studies. Table 4. Meta-analysis of interleukin 8 -251T/A polymorphism in prostate cancer. Association of Three Gene Variants with Risk of PCa-Chen et al. Vol 12 No 03 May-June 2015 2141 fixed effect model or random effect model was per- formed for assessing the pooled OR. Overall, the fre- quency of C allele is a little bit higher in PCa cases than that in the healthy controls (36.1% vs. 34.7%). However, there was no evidence for a significant as- sociation between XPC gene 939A/C polymorphism and PCa risk in the whole population (C vs. A, 0R = l.06, 95% CI: 97-1.15, P = .22; CC vs. AA, 0R = l.19, 95% CI: 0.85-1.68, P = .32; CC + AC vs. AA, OR = l.03, 95% CI: 0.92-1.17, P = .59; CC vs. AC + AA, OR = l.20, 95% CI: 0.85-1.70, P = .30) (Figure 2). We also evaluated the effect of the polymorphism by eth- nicity. We did not detect a significant association be- tween XPC gene 939A/C polymorphism and PCa risk in Asians, Caucasians, or African population (P > .05). Association between IL8 -251 T/A Polymorphism and PCa Risk Table 4 demonstrates the summary of all genetic com- parisons between IL8 -251 T/A polymorphism and PCa risk. As shown in Figure 3, the result demonstrated that the variant A allele did not have a significant increased risk of PCa compared with those individuals without A allele (A vs. C; OR = l.0l, 95% CI: 0.92-1.10, P = .88). No significant association was found in other genetic mod- els (AA vs. TT, OR = l.03, 95% CI: 0.86-1.23, P = .75; Table 5. Meta-analysis of mouse double minute 2 (MDM2) homolog gene -309T/G polymorphism in prostate cancer. Variables Comparison No. OR (95% CI) P Value* Z Ph** I2 (%) Model Overall G vs. T 6 0.89 (0.76-1.05) .17 1.37 0.04 56 R GG vs. TT 6 0.81 (0.56-1.17) .25 1.14 0.02 62 R GG + GT vs. TT 6 0.84 (0.67-1.06) .14 1.47 0.07 52 R GG vs. GT + TT 6 0.96 (0.80-1.16) .69 0.40 0.10 46 F Asian G vs. T 2 1.00 (0.82-1.22) .00 0.00 0.17 46 F GG vs. TT 2 1.04 (0.69-1.56) .86 0.18 0.25 23 F GG + GT vs. TT 2 0.96 (0.54-1.70) .89 0.14 0.07 69 R GG vs. GT + TT 2 1.03 (0.73-1.46) .86 0.17 0.77 0.0 F Caucasians G vs. T 4 0.85 (0.68-1.06) .14 1.47 0.03 67 R GG vs. TT 4 0.71 (0.41-1.20) .20 1.29 0.01 73 R GG + GT vs. TT 4 0.80 (0.60-1.05) .10 1.62 0.08 55 R GG vs. GT + TT 4 0.83 (0.54-1.27) .39 0.87 0.03 67 R Abbreviations: OR, odds ratio; CI, confidence interval. No, number of included studies. * P value for overall effect. ** P value for heterogeneity among studies. Figure 2. Forest plot on the association between C allele in xeroderma pigmentosum group C gene and risk of prostate cancer. Association of Three Gene Variants with Risk of PCa-Chen et al. Review 2142 AA + AT vs. TT, OR = 0.99, 95% CI: 0.79-1.24, P = .90; AA vs. AT + TT, OR = l.02, 95% CI: 0.88-1.17, P = .80). Association between MDM2 -309T/G Polymorphism and PCa Risk The overall analysis of the studies concerning MDM2 polymorphism and PCa risk is shown in Table 5, which revealed no significant association between MDM2 309T/G polymorphism with PCa risk in any genetic models (G vs. T, OR = 0.89, 95% CI: 0.76-1.05, P = .17; GG vs. TT, OR = 0.81, 95% CI: 0.56-1.17, P = .25; GG + GT vs. TT, OR = 0.84, 95% CI: 0.67-1.06, P = .14; GG vs. GT + TT, OR = 0.96, 95% CI: 0.80-1.16, P = .69) as shown in Figure 4. In subgroup analysis based on ethnicity, we found that MDM2 309T/G vari- ant did not significantly increase the risk of PCa neither in Asian (P > .05) nor in Caucasians (P > .05) popula- tion, no matter what kind of genetic model was used. Sensitivity Analyses and Publication Bias Each included study was deleted every time to ver- ify whether the individual data influenced the ORs. Figure 3. Meta-analysis of the association between interleukin 8 -251T/A polymorphism and risk of prostate cancer. Our results showed that the pooled ORs were not sig- nificantly changed, confirming the stability of our overall result. The funnel plots did not show any ob- vious asymmetry, further indicating that there was no publication bias in our meta-analysis (Figure 5). DISCUSSION The present meta-analysis examined the association between three commonly studied gene polymorphisms XPC 939AIC, IL8 -251T/A, and MDM2 -309T/G with PCa risk. Eighteen separate articles including 5725 PCa cases and 5900 healthy controls were retrieved in the final analysis. Overall we did not detect a signif- icant association between these three gene polymor- phisms with PCa in any genetic models. Similar re- sults were found in stratification analyses by ethnicity. The XPC gene contains 16 exons and 15 introns. It can interact with RAD23B to form a XPC-RAD23B com- plex, specifically involving in global genome repair and works as the earliest damage detector to initiate the NER pathway.(45) Studies have proved that XPC is Figure 4. Forest plot of mouse double minute 2 (MDM2) homolog gene -309T/G polymorphism with risk of prostate cancer under each genetic models. Association of Three Gene Variants with Risk of PCa-Chen et al. Vol 12 No 03 May-June 2015 2143 a key component of the NER pathway that participates in DNA damage repair.(46) Mutations in this gene, result in xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sun- light and the development of skin cancer at an early age.(47) XPC polymorphisms have been associated with increased risk of many human cancers such as bladder cancer,(48) and digestive system cancers.(49) Our results was consistent with previous meta-analysis conducted by Zou and colleagues in which screened out five stud- ies including 1966 cases and 1970 controls, demonstrat- ed that this variant was not associated with PCa risk.(50) IL8 is one of key members of the human a-chemok- ine subfamily, and acts as a potent chemoattractant and activator of neutrophils.(51) It is produced by normal cells including monocytes, neutrophils, fibroblasts, and endothelial cells. IL8 is involved in thrombophilia and angiogenesis, and highly expressed in various human cancers. It also plays an important role in chronic in- fection, inflammation, and cancer development, and its overexpression may implicate the increased sus- ceptibility or the modulated clinicopathological fea- tures for different cancers.(52) The corresponding gene polymorphisms may lead to the aberrant expression of IL8 and accordingly increase the risk of cancers. The -251T/A polymorphism is a T-to-A substitution that oc- curs at nucleotide -251, and the less A allele can lead to the increased expression of IL8. Xue and colleagues found that IL8 -251 AA genotype is associated with the overall risk of developing gastric cancer and may seem to cause more susceptibility to gastric cancer in Asian populations.(14) Andia and colleagues demon- strated that IL8 gene promoter polymorphism (rs4073) may contribute to chronic periodontitis.(53) Wang and colleagues reported that IL8 -251T/A polymorphism is associated with a significantly increased risk of cancers and may provide evidence-based medical certificate to study the cancer susceptibility.(54) However, no con- nection was found with PCa risk in our meta-analysis. MDM2 is a major regulator of p53 function. It is well known that the functional role of MDM2 is related to the negative regulation of tumor suppressor p53. It acts with P53 in a feedback loop where p53 activates MDM2 at the transcriptional levels while MDM2 binds, inhibits and degrades the p53 protein through E3 ligase activity.(55) Studies have shown that MDM2 antagonists-activated wild-type p53 in combination with androgen depletion may provide an efficacious approach to PCa therapy.(56) The functional importance of this interaction is illustrated by the findings that re- duction of the MDM2 expression level inhibits tumor formation in mice while depletion of the MDM2 gene leads to embryonic lethality, an effect rescued by con- comitant p53 deletion.(57) MDM2 amplification and/ or protein over expression has been observed in many human cancers harboring wild-type TP53, the gene coding for the p53 protein,(58) and MDM2 over expres- sion has been suggested to act as an alternative mech- anism to p53 inactivation, promoting tumor growth.(59) The MDM2 gene plays a key role in the p53 pathway, and the SNP 309T/G in the promoter region of MDM2 has been shown to be associated with increased risk of cancer. However, we did not find a relationship be- tween this polymorphism and PCa risk. Previous me- ta-analysis covering 4 independent studies showed no significant association between MDM2 309T/G pol- ymorphism and PCa risk in whole analysis as well.(60) Several limitations in this meta-analysis should be acknowledged. Firstly, the subgroups may have a relatively lower power based on a small number of studies. Secondly, other covariates such as age, sex and smoking status should be included to get a more precise result. Thirdly, other genes which may interact with these genes should be considered. CONCLUSION In conclusion, our results demonstrated that XPC, IL8, and MDM2 variants were not associated with increased risk of PCa. Further large scale studies with different populations and ethnicities are need- ed to confirm our results. 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