|Year : 2019 | Volume
| Issue : 8 | Page : 60-68
Association between androgen receptor gene polymorphisms and testicular germ cell tumor: A systematic review and meta-analysis
Jiaxuan Qin1, Ni Cui2, Ruida Hou1, Tie Liu3, Hongyan Sun3, Yi Liu3, Lei Wang3, Jinsong Ni4, Xinquan Gu1
1 Department of Urology Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
2 Department of Clinical Medicine, Bethune Medical School, Jilin University, Changchun, Jilin, China
3 Department of Tissue Bank, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
4 Department of Pathology, The First Clinical Hospital of Jilin University, Changchun, Jilin, China
|Date of Web Publication||22-Mar-2019|
Prof. Xinquan Gu
Department of Urology Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin
Source of Support: None, Conflict of Interest: None
Objective: To estimate association between androgen receptor (AR) gene polymorphisms and testicular germ cell tumor (TGCT) susceptibility.
Materials and Methods: Systematic search of studies on the association between AR gene polymorphisms and TGCT susceptibility was conducted. Odds ratios and 95% confidence intervals were used to pool effect size.
Results: For CAG repeat, no evidence was found for association between (>25 vs. ≤25), (>25 vs. 21–25), (<21 vs. 21–25), (others vs. 21–25), (>23 vs. ≤23), (<21 vs. ≥21), (<21 vs. ≥21)'s some subgroups and TGCT susceptibility, which showed stability. In (>24 vs. ≤24), (>24 vs. 21–24), (<21 vs. 21–24), and (others vs. 21–24) and almost all of their subgroups, increased TGCT risk was found without sensitivity analysis. For GGN, no statistical change of TGCT risk was found in (<23 vs. ≥23), (<23 vs. 23), which showed stability. For single nucleotide polymorphism (SNP) rs6152 G > A, rs1204038 G > A and rs2361634 A > G, no statistical change was found without sensitivity analysis.
Conclusions: GGN repeat number <23 may not be associated with TGCTs susceptibility. However, there was insufficient data to fully confirm association in GGN repeat number >23, CAG repeat number, SNP rs6152, rs1204038, and rs2361634.
Keywords: Androgen receptor, meta-analysis, polymorphism, testicular germ cell tumor
|How to cite this article:|
Qin J, Cui N, Hou R, Liu T, Sun H, Liu Y, Wang L, Ni J, Gu X. Association between androgen receptor gene polymorphisms and testicular germ cell tumor: A systematic review and meta-analysis. J Can Res Ther 2019;15, Suppl S1:60-8
|How to cite this URL:|
Qin J, Cui N, Hou R, Liu T, Sun H, Liu Y, Wang L, Ni J, Gu X. Association between androgen receptor gene polymorphisms and testicular germ cell tumor: A systematic review and meta-analysis. J Can Res Ther [serial online] 2019 [cited 2021 Jun 21];15:60-8. Available from: https://www.cancerjournal.net/text.asp?2019/15/8/60/181175
| > Introduction|| |
The incidence rate of testicular cancer has been increasing in many countries for several decades, and the increase is mostly in seminomas. Worldwide, the risk of developing testicular cancer is highest among men living in the United States and Europe. More than 90% of cancers of the testicle develop in germ cells. The two main types of testicular germ cell tumor (TGCT) in men are seminomas and nonseminomas (embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, and/or teratoma).
It has been suggested that testicular cancer, poor semen quality, undescended testis, and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which is a result of disruption of embryonal programming and gonadal development during fetal life., The onset of TDS, including TGCT, may be due to an imbalance of steroidal sex hormones. Testosterone is the major circulating androgen and is converted to the more potent androgen dihydrotestosterone (DHT). Testosterone and DHT mediate their effects through binding and activating androgen receptor (AR). Moreover, it has been suggested that endocrine-disrupting chemicals might be associated with TDS. Polymorphisms in AR might modulate gene–environment interactions, potentially increasing the effects of endocrine-disrupting agents.
CAG trinucleotide repeat region, (CAG)n CAA, is located in AR gene's N-terminal transactivation domain (NTD) which encodes a polyglutamine (polyQ) tract in AR protein. Appropriate polyQ tract length is critical for maintenance of N/C interaction which can affect AR function., CAG repeat expansion in the region can also reduce AR mRNA and protein expression. GGN trinucleotide repeat region, (GGT)3 GGG (GGT)2(GGC)n, is also located in AR gene's NTD; however, the functional effect of GGN polymorphism remains unclear. Several single nucleotide polymorphisms (SNPs) in AR gene have been studied as well.
Association between AR gene polymorphisms and TGCT susceptibility has been studied in several populations. Sample sizes in these studies are relatively small. Therefore, we decided to perform a systematic review and meta-analysis to estimate it.
| > Materials and Methods|| |
Identification of eligible studies
Two investigators carried out a systematic search independently in PubMed, Embase, Ovid MEDLINE (R), Cochrane Library, clinicaltrials.gov, CBM, China National Knowledge Infrastructure (CNKI), WanFangData (one China database), and CQVIP (one China database) databases. The following terms were used: “AR OR AR,” “polymorphism OR polymorphisms,” and “cancer of testis OR carcinoma of testis OR testicular cancer OR testis cancer OR ball cancer OR testicular epidermoid OR testis neoplasm OR germ cell cancer OR germ cell tumor OR TGCT OR spermatocytoma OR spermocytoma OR seminoma OR nonseminomatous germ cell tumor OR NSGCT OR embryonal carcinoma OR yolk sac tumor OR teratoma OR trophoblastic tumor OR choriocarcinoma OR mixed germ cell tumor,” without any limitation applied. The last search update was performed on May 26, 2015. References of related studies and reviews were also manually searched for additional studies.
Inclusion and exclusion criteria
Studies selected in this systematic review and meta-analysis must meet following inclusion criteria: (1) evaluation of the association between AR gene polymorphisms and TGCT; (2) case–control study; (3) studies focusing on tissues of human beings, not cell lines; (4) testicular germ cell cancer (TGCC) diagnosed; (5) detailed genotype data could be acquired to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs); exclusion criteria: (1) duplication of previous publications; (2) comment, review, and editorial; and (3) study without detailed genotype data. When there were multiple publications from the same population, only the largest study was included.
Study selection was achieved by two investigators independently, according to the inclusion and exclusion criteria by screening title, abstract, and full-text. Any dispute was solved by discussion.
Data of the eligible studies were extracted by two investigators independently. In the case of a conflict, an agreement was reached by discussion. If the dissent still existed, the third investigator would be involved to adjudicate the disagreements.
The following contents were collected: first author's surname, year of publication, the characteristics of cases and controls, source of control groups, country of origin, the detective sample, ethnicity, genotyping method, and detailed genotype data.
Methodological quality assessment
The qualities of included studies were evaluated independently by two investigators. According to Newcastle–Ottawa Scale and the most important factor was “age and country.” Quality scores range from 0 to 9, and higher scores mean better quality of the study. The disagreement was resolved through discussion.
Our systematic review and meta-analysis were conducted according to PRISMA checklists. OR and 95% CIs were calculated to evaluate the strength of association between AR gene polymorphisms and TGCC. Pooled ORs were obtained from a combination of single studies. The statistical significant level was determined by Z-test with P value of ORs (POR) < 0.05.
Heterogeneity was evaluated by Q-test and I2 index. When Q-test's P value of heterogeneity (PH) < 0.10 and/or I2 index was more than 50%, random-effects model (DerSimonian and Laird method) was used; otherwise, fixed-effects model (Mantel and Haenszel method) was conducted. Sensitivity analyses were performed toward each genetic model to evaluate the effect of each study on combined ORs by sequentially excluding each study in total and in any subgroup including more than two studies. Besides, subgroup analyses were stratified by control type, cancer type, tumor stage, and cryptorchidism. Potential publication bias was checked by Begg's funnel plots and Egger's test., An asymmetric plot, the P value of Begg's test (PB) < 0.05, and the P value of Egger's test (PE) < 0.05 were considered a significant publication bias. All statistical analyses were performed with Stata 12.0 software (StataCorp, College Station, Texas, USA). A two-tailed P < 0.05 was considered significant except for specified conditions, where a certain P value was declared.
| > Results|| |
Characteristics of studies
A total of 214 articles were acquired from databases and other sources (PubMed = 74, Embase = 36, Ovid MEDLINE (R) = 18, Cochrane = 0, clinicaltrials.gov = 0, CBM = 0, CNKI = 85, WanFangData = 0, CQVIP = 0, and other sources = 1). The one article Garolla et al. from “other sources” was acquired through manually searching references lists of reviews. The selection process was shown in [Figure 1]. Twelve articles were full-text reviewed and 1 article was excluded for duplication of previous publications. Finally, 11 articles,,,,,,,,,, were included in our systematic review and meta-analysis. The characteristics of each study are shown in [Table 1] and [Table 2]. All included studies were carried out in Caucasian. Different genotyping methods were utilized including sequencing and capillary electrophoresis for trinucleotide repeat length polymorphisms, and TaqMan PCR, MassARRAY, sequencing for SNP. The control type was population-based (PB) in all studies except for Garolla et al., which was hospital-based. Blood samples were used for genotyping in all studies except for Figueroa et al. and Davis-Dao et al. In Figueroa et al., buccal cell specimens were used for genotyping. In Davis-Dao et al., both blood sample and mouthwash sample were used.
|Table 1: Characteristics of studies about CAG and GGN repeat length polymorphism included in the systematic review and meta-analysis|
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|Table 2: Characteristics of studies about androgen receptor gene single-nucleotide polymorphisms included in the meta-analysis|
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According to the cutoff length of CAG repeat, we evaluated these comparisons: (>25 vs. ≤25), (>25 vs. 21–25), (<21 vs. 21–25), (others vs. 21–25), (>24 vs. ≤24), (>24 vs. 21–24), (<21 vs. 21–24), (others vs. 21–24), (>23 vs. ≤23), and (<21 vs. ≥21). For GGN repeat, the cutoff length was 23 in all studies involved and these comparisons were evaluated: (>23 vs. ≤23), (<23 vs. ≥23), (>23 vs. 23), (<23 vs. 23), and (others vs. 23).
Meta-analysis of SNP rs6152 G > A, rs1204038 G > A, and rs2361634 A > G were performed. In addition, SNP A645D, rs1337080 G > A, rs962458, rs2207040, rs1204039, rs7061037, rs12014709, and rs5031002 were studied once, and only rs12014709 showed significantly increased cancer risk in Swedish and overall.
Subgroup analyses were stratified by control type, cancer type, tumor stage, and cryptorchidism.
Overall analyses and subgroup analyses
For CAG repeat length, significant statistical heterogeneity was found in some comparisons and subgroups [Table 3] so that random-effects model was used. Significantly increased TGCT risk was found in comparison (>24 vs. ≤24), (>24 vs. 21–24), (<21 vs. 21–24), (others vs. 21–24), and in some of their subgroups [Table 3].
|Table 3: Summary of pooled odds ratios in meta-analysis of CAG repeat length polymorphism|
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For GGN repeat length, significant heterogeneity was found in some subgroups [Table 4] and a random-effects model was used. Significantly increased TGCT risk was found in comparison (>23 vs. ≤23) and its three subgroups [Table 4], [Figure 2] and [Figure 3].
|Table 4: Summary of pooled odds ratios in meta-analysis of GGN repeat length polymorphism and single-nucleotide polymorphisms|
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|Figure 2: Forest plot with a fixed-effects model for the association between testicular germ cell cancer risk and GGN repeat number in >23 versus ≤23: subgroup analyses by control type. For each study, the estimate of odds ratio and its 95% confidence interval is plotted with a box and a horizontal line. Rhombus: Pooled odds ratio and its 95% confidence interval|
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|Figure 3: Forest plot with a fixed-effects model for the association between testicular germ cell cancer risk and GGN repeat number in >23 versus ≤23: Subgroup analyses by cancer type|
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For SNP rs6152 G > A, rs1204038 G > A, and rs2361634 A > G, no significant heterogeneity was found and no significant association between these SNPs and TGCT susceptibility was identified in the fixed-effects model [Table 4].
Sensitivity analyses were performed in any comparison and any subgroup including more than two studies. For CAG repeat length, statistically similar results were obtained in any comparison and any subgroup whose sensitivity analysis could be made, suggesting the stability of these meta-analyses.
For GGN repeat length, when study No. 25 was excluded, statistically different results were obtained in (>23 vs. ≤23) comparison (OR = 1.191, 95% CI = 0.997–1.423) and in this comparison's PB (OR = 1.182, 95% CI = 0.978–1.428) and cryptorchidism (−) and (?) (OR = 1.166, 95% CI = 0.937–1.453) subgroups. When study No. 24 was excluded, statistically different results were obtained in (>23 vs. ≤23) comparison's seminoma subgroup (OR = 1.298, 95% CI = 1.010–1.669), (>23 vs. 23) comparison (OR = 1.310, 95% CI = 1.008–1.703), and (others vs. 23) comparison (OR = 1.297, 95% CI = 1.015–1.657). Result of (>23 vs. ≤23) comparison's PB subgroup was also affected by study No. 23. Furthermore, result of (>23 vs. ≤23) comparison's cryptorchidism (−) and (?) subgroup was also affected by study No. 22 (−) and No. 26 [Table 4].
For SNP rs6152 G > A, rs1204038 G > A, and rs2361634 A > G, sensitivity analyses could not be performed.
Begg's funnel plot and Egger's test were used to assess the publication bias. Overall, the symmetry of funnel plot, P value of Begg's test (PB), and P value of Egger's test (PE) were evaluated in >23 versus ≤23 comparison of GGN repeat length (PB= 0.624, PE= 0.100) and funnel plot was roughly symmetrical. However, only five studies were included in this comparison so that the efficiency of the tests might not be that good. No Begg's funnel plot or Egger's test was performed for any other comparison and any subgroup owing to the limited number of included studies.
| > Discussion|| |
For CAG repeat length, no evidence was found for the association between comparison (>25 vs. ≤25), (>25 vs. 21–25), (<21 vs. 21–25), (others vs. 21–25), (>23 vs. ≤23), (<21 vs. ≥21), (<21 vs. ≥21)'s some subgroups, and TGCT susceptibility, and the results showed stability in sensitivity analyses. In these comparisons' other subgroups, no statistically change of TGCT risk was found either, but sensitivity analyses could not be done. In comparison (>24 vs. ≤24), (>24 vs. 21–24), (<21 vs. 21–24), (others vs. 21–24), and almost all of their subgroups, significantly increased TGCT risk was found; however, no sensitivity analysis could be done either. Because of insufficient studies included and insufficient comparisons could be made, it is hard to tell: if the results about cutoff length 24 were meaningful and different cutoff length caused different results, if (>23 vs. 21–23), (<21 vs. 21–23) still showed no association, and if other different cutoff length of CAG repeat could affect the results. Moreover, studies included in comparisons about cutoff length 24 were different from cutoff length 25, which increased the difficulty of results analyses.
For GGN, the cutoff length mostly was 23. No statistical change of TGCT risk was found in comparison (<23 vs. ≥23), (<23 vs. 23) and the results showed stability. In comparison (>23 vs. 23) and (others vs. 23), no statistically change was found either, but the results were affected by study No. 24. In (>23 vs. ≤23) and its some subgroups, increased TGCT risk was found and the results were not that stable. For SNP rs6152 G > A, rs1204038 G > A, and rs2361634 A > G, no statistical change was found but sensitivity analyses could not be performed. These unstable or relatively unreliable results should be interpreted with caution.
Meanwhile, the limitations of this systematic review and meta-analysis need to be addressed. To date, the number of available studies which can be included in this systematic review and meta-analysis were small. Data for subgroup analyses were scanty. Seven nongerm cell tumors were included in all 123 cases in Garolla et al. and histology is unknown for 12 TGCT cases in Davis-Dao et al., which may affect results in some degree if significant differences existed in cancer type. Cryptorchidism, also called “undescended testicle(s),” is one of the main risk factors for testicular cancer. However, cases with cryptorchidism were involved in some studies [Table 1], which may affect results in some degree. Related studies published in other languages or unpublished were possibly missed.
| > Conclusions|| |
Our results suggested that GGN repeat number <23 may not be associated with the susceptibility of TGCT. However, there were insufficient data to fully confirm the association between GGN repeat number >23, CAG repeat number, SNP rs6152, rs1204038, rs2361634, and TGCT, and the results should be interpreted with caution. Well-designed studies with larger sample size and more subgroups are required to validate the risk identified in the current meta-analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: An increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16:972-8.
Rajpert-De Meyts E. Developmental model for the pathogenesis of testicular carcinoma in situ
: Genetic and environmental aspects. Hum Reprod Update 2006;12:303-23.
Martin OV, Shialis T, Lester JN, Scrimshaw MD, Boobis AR, Voulvoulis N. Testicular dysgenesis syndrome and the estrogen hypothesis: A quantitative meta-analysis. Environ Health Perspect 2008;116:149-57.
Aschim EL, Oldenburg J, Kristiansen W, Giwercman A, Witczak O, Fosså SD, et al.
Genetic variations associated with the effect of testicular cancer treatment on gonadal hormones. Hum Reprod 2014;29:2844-51.
Gilbert D, Rapley E, Shipley J. Testicular germ cell tumours: Predisposition genes and the male germ cell niche. Nat Rev Cancer 2011;11:278-88.
Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994;22:3181-6.
Buchanan G, Yang M, Cheong A, Harris JM, Irvine RA, Lambert PF, et al.
Structural and functional consequences of glutamine tract variation in the androgen receptor. Hum Mol Genet 2004;13:1677-92.
Choong CS, Kemppainen JA, Zhou ZX, Wilson EM. Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol 1996;10:1527-35.
Jääskeläinen J. Molecular biology of androgen insensitivity. Mol Cell Endocrinol 2012;352:4-12.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. J Clin Epidemiol 2009;62:1006-12.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-58.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-101.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
Garolla A, Ferlin A, Vinanzi C, Roverato A, Sotti G, Artibani W, et al.
Molecular analysis of the androgen receptor gene in testicular cancer. Endocr Relat Cancer 2005;12:645-55.
Chia VM, Li Y, Quraishi SM, Graubard BI, Figueroa JD, Weber JP, et al.
Effect modification of endocrine disruptors and testicular germ cell tumour risk by hormone-metabolizing genes. Int J Androl 2010;33:588-96.
Rajpert-De Meyts E, Leffers H, Daugaard G, Andersen CB, Petersen PM, Hinrichsen J, et al.
Analysis of the polymorphic CAG repeat length in the androgen receptor gene in patients with testicular germ cell cancer. Int J Cancer 2002;102:201-4.
Giwercman A, Lundin KB, Eberhard J, Ståhl O, Cwikiel M, Cavallin-Ståhl E, et al.
Linkage between androgen receptor gene CAG trinucleotide repeat length and testicular germ cell cancer histological type and clinical stage. Eur J Cancer 2004;40:2152-8.
Västermark Š, Giwercman YL, Hagströmer O, Rajpert De-Meyts E, Eberhard J, Ståhl O, et al.
Polymorphic variation in the androgen receptor gene: Association with risk of testicular germ cell cancer and metastatic disease. Eur J Cancer 2011;47:413-9.
Kristiansen W, Aschim EL, Andersen JM, Witczak O, Fosså SD, Haugen TB. Variations in testosterone pathway genes and susceptibility to testicular cancer in Norwegian men. Int J Androl 2012;35:819-27.
Grassetti D, Giannandrea F, Paoli D, Masciandaro P, Figura V, Carlini T, et al.
Androgen receptor polymorphisms and testicular cancer risk. Andrology 2015;3:27-33.
Biggs ML, Davis MD, Eaton DL, Weiss NS, Barr DB, Doody DR, et al.
Serum organochlorine pesticide residues and risk of testicular germ cell carcinoma: A population-based case-control study. Cancer Epidemiol Biomarkers Prev 2008;17:2012-8.
Davis-Dao CA, Siegmund KD, Vandenberg DJ, Skinner EC, Coetzee GA, Thomas DC, et al.
Heterogenous effect of androgen receptor CAG tract length on testicular germ cell tumor risk: Shorter repeats associated with seminoma but not other histologic types. Carcinogenesis 2011;32:1238-43.
Figueroa JD, Sakoda LC, Graubard BI, Chanock S, Rubertone MV, Erickson RL, et al.
Genetic variation in hormone metabolizing genes and risk of testicular germ cell tumors. Cancer Causes Control 2008;19:917-29.
Kristiansen W, Andreassen KE, Karlsson R, Aschim EL, Bremnes RM, Dahl O, et al.
Gene variations in sex hormone pathways and the risk of testicular germ cell tumour: A case-parent triad study in a Norwegian-Swedish population. Hum Reprod 2012;27:1525-35.
Lundin KB, Nordenskjöld A, Giwercman A, Giwercman YL. Frequent finding of the androgen receptor A645D variant in normal population. J Clin Endocrinol Metab 2006;91:3228-31.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]