Abstract

Background: Chromosome Xq11-12 is the place that the androgen receptor (AR) sequence appears. Herein, the prevalence of this biomarker and its relation with pT stage and tumor grade was reported.


Methods: Four online sites (PubMed, Scopus, Web of Science, and Cochrane Library) have been searched up to Sep 2018 systematically. Meta-Analysis software version 2.0 (CMA 2.0) and STATA 14.0 statistical software were utilized. Publication bias did not exist.


Results: From the initial 1141 articles identified from the systematically searches. At last, nine of them remained for analysis. The meta-analysis included 1447 patients that 345 of them had AR expression. AR expression significantly correlated with low tumor grade and low tumor pT stage.


Conclusion: AR expression was 28.2%, and it had the relationship with tumor low grade and low pT stage. Additional studies required to figure out the role of it on RCC patients.

Keywords: AR Grade pT stage RCC


Introduction

Renal cell carcinoma (RCC) is the foremost different urological malignancy among adults 1. The most prevalent form of malignancy RCC is clear cell RCC (ccRCC) and represents over 90% of malignant kidney tumors 2. The androgen receptor (AR) sequence is found at chromosome Xq11-12 and includes of eight exons 3. Prevalence of the AR is appeared in several parts of the body, principally in sexual parts of men. Also, it was reported in breast, bladder, liver, gastrointestinal 4. High AR expression is potential prognosis factor in bladder cancer 5, and it created longer life in patients with serous carcinoma of the ovary 6, an agent for progressive the squamous cell carcinoma of head and neck 78. We tend to are responsive to only rare studies evaluating AR immunohistochemical staining in RCC 91011. Though the targeted therapy creates an effective route for advanced RCC patients 12, the relationship between AR expression and RCC progression stay uncertain until now 13. This meta-analysis reports the expression of AR and its relation with some pathological factors in RCC.

Methods

Search Strategy

PubMed, Scopus, Web of science, and Cochran library included in this study. Search terms included systematically up to September 2018 were “androgen receptor”, “AR”, “kidney”, “renal cell carcinoma”, “cancer”, “carcinoma”, and “tumor. The studies were searched for the assessment of expression of the AR in RCC patients in English abstract.

Inclusion and Exclusion Criteria

Inclusion criteria:

1) Cohort studies

2) Human studies

Exclusion criteria:

1) Case-control, case report, and review studies; conference paper and letter to editor

2) The study with incomplete data

Data extraction

First author, year of publication, nation, RCC samples, expression, grade, pT stage, number of males, and the mean age were extracted. We could not have analysis on types of survival as a result of the studies didn't have the same data.

Statistical analysis

Comprehensive Meta-Analysis software version 2.0 (CMA 2.0) and STATA 14.0 statistical software (StataCorp LP, College Station, TX, USA) were used for random-effect analysis. P-value (2-sided) <0.05 is significant.

CMA 2.0

The event rate (ER) with 95% confidence interval (95% CI) was calculated for estimation of the expression of AR mutations in RCC patients. Begg’s and Egger’s tests were calculated for bias.

STATA 14.0

P<0.1 is significant for heterogeneity. Heterogeneity is assessed by the Q and I 2 statistics.

Results

After primary searches, 1141 articles identified. Twenty one studies remained after we excluded the non-relevant studies. Then, twelve studies were removed based on reasons (five conference papers, three reviews, two articles without full text, one letter to editor, and one database). At last, nine of them remained for analysis (Figure 1).

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Figure 1 . Flow chart of studies reviewed and included in the present meta‑analysis.

From nine studies 91011141516171819, two studies 1417 were Germany, two studies 1519 were USA and others were from Austria 9, Korea 10, China 11, Italy 16 and Japan 18. From 1447 patients 91011141516171819, 345 AR expression exist. One hundred seventy-one cases in four studies 9101118 of meta-analysis study were male, and 59 cases were female (sum=202). Mean age (min-max) in two studies was 60.06 (29-82). Three studies 9111418 on pT stage in 132 patients with expression AR showed 51 cases pT stage 1, 20 cases pT stage 2, 41 cases pT stage 3. And also, 160 low grade versus 42 high-grade cases exist in four studies 9101118 (Table 1).

Table 1.

The information about studies of the meta-analysis

First Author (year) Nation Patients Total androgen expression Sex pT Stage Grade AgeMean (Min – Max)
Male Female Low High Low High
Langner C, 2004 9 Austria 182 27 24 3 102(24) 80(3) 99(21) 83(6) -
Noh SJ, 2013 10 Korea 200 126 93 33 - - 158(101) 42(25) 58.13 29–82)
Foersch S, 2017 14 Germany 546 69 - - 348(64) 198(36) 463(NA) 83(NA) --
Williams EM, 2015 15 USA 307 57 - - - - - - --
Zhu G, 2014 11 China 120 36 24 12 95(34) 25(2) 89(32) 31(4) 63 (35-82)
Concolino G, 1981 16 Italy 14 8 - - - - - - --
Klotzl G, 1987 17 Germany 20 3 - - - - - - --
Nakano E, 1984 18 Japon 41 13 30 11 - - 20(6) 21(7) - (46-76)
Brown DF, 1998 19 USA 17 6 - - - - - - --

AR Expression

The prevalence of AR expression in RCC patients has been reported in Figure 2 by the ER. The pooled ER of the studies was 28.2% (95% CI=16.3%-44.3%; P=0.009). The Begg’s and Egger’s tests didn’t show publication bias (P=0.53 and P=0.75, respectively) (Figure 3).

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Figure 2 . Forest plot of OR for expression in RCC patients . Horizontal line represents 95% CI of each study. The diamond indicates the pooled OR value. OR: odds ratio; CI: confidence interval.

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Figure 3 . Funnel plot for potential publication bias of expression of RCC.

AR expression and tumor grade

Among three studies (502 cases), heterogeneity was existed (I2 = 85.80%, p =0.0) in a fixed‑effects model. Correlation between AR expression and low grade was positive (OR, 1.98; 95% CI, 1.44-2.71; P<0.01) (Figure 4).

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Figure 4 . Forest plot of OR for tumor grade. Horizontal line represents 95% CI of each study. The diamond indicates the pooled OR value. OR : odds ratio; CI : confidence interval.

AR and pT stage

Among three studies (848 cases), heterogeneity was not existed (I2 = 4.3%, p = 0.353). Correlation between AR expression and low pT-stage was positive (OR, 4.04; 95% CI, (3.10-5.26); P< 0.01) (Figure 5).

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Figure 5 . Forest plot of OR for pT stage . Horizontal line represents 95% CI of each study. The diamond indicates the pooled OR value. OR: odds ratio; CI: confidence interval.

Discussion

Radiotherapy, chemotherapy, and immunotherapy used for treat metastatic RCC patients 12. But, a lot of controversial for treatment of this malignancy are existed until now 1317. Moreover, AR expression has been related to chemo-responsiveness 20. Exaggerated AR expression was related to attenuate responsiveness and exaggerated migration of tumor cells 21. The clear cell RCC resists chemotherapy and radiation with a restricted therapeutic period of the anti-angiogenesis targeted therapy (6–15 months) 22. Clinical researchers have disclosed that some patients reply to endocrine therapy objectively or subjectively 2324. AR can help to the pathobiology of breast malignancy 25, and maybe inhibition of androgen sign had a therapeutic role in it 26. Firstly, AR was observed in cancerous renal tissues and then appears in other urinary organs like prostate and then breast cancer 27. Nakano et al., who noted that patients with RCC showing immunoreactivity for one or a lot of hormone receptors (ER, PR and/or AR) had a considerably higher survival rate 18. A cohort found that AR expression in clear cell RCC was prognostic which high expression 28. Cut off for express AR reported from 12.9% to 100% 293031. AR expression found in non-invasive urothelial malignancies as compared to invasive urothelial malignance 3233.

Consequently, AR immunoreactivity was related to renowned favorable prognostic factors, like tiny tumor size, low pT stage (more than 30% in pT1a tumors) in addition as low histological grade 34. The AR-positive rate ranged from 16.3%-44.3% in RCC tissues in this study. Noh et al., 10 and Concolino et al., 16 showed the level of AR-positive is higher than our meta-analysis. In other hands Langne et al., 9 and Klotzl et al., 17 demonstrated that the AR-positive is lower than in this study among RCC patients. Nine studies (1,447 cases) surveyed for AR expression in RCC patients in the meta-analysis and also expressed relationship tumor grades and pT stages with it. Zhu et al., 11 incontestable that AR expression rate was negatively accompanied pT stage and Fuhrman’s grade in RCC patients. Also, this relationship was indicated by Foersch et al., 14 and Langner et al. 9, Zhu et al., 11 reported prevalence of AR had a negative relationship with pT stage and grade in RCC patients. Foersch et al., 14 and Langner et al., 9 reported the results opposite of him. Noh et al., 10 said AR expression related with the histological nuclear grade (p<0.027) and TNM stage (p<0.002). The meta-analysis showed AR expression correlated with low grade and pT stage positively.

C onclusion

As our knowledge, this study is first meta-analysis to research the impact of AR expression on RCC patients. The current study showed the level of expression of AR and its relative with tumor grade and pT stage in RCC patients. Additional studies are needed to the role of AR expression in these patients.

Competing Interests

The author(s) declared no conflicts of interest.

Authors' Contributions

Conceptualization: ES MP

Formal analysis: ES

Methodology: ES HA

Project administration: ES MP HA HM

Software: ES

Validation: HM HA

Writing — original draft: ES

Writing — review & editing: ES MP HA HM

Abbreviations

AR: Androgen Receptor

ccRCC: Clear Cell Renal Cell Carcinoma

CI: Confidence Interval

ER: Estrogen Receptor pT Stage: Pathologic Tumor Stage PR: Progesterone Receptor RCC: Renal Cell Carcinoma

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