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Background: Prostatic epithelial cells synthesize the active form of vitamin D (1,25-dihydroxyvitamin D ), which participates in regulat- ing prostate growth. Calcitriol, a synthetic form of vitamin D , exhibits antiproliferative and prodifferentiation activities in prostate cancer. The function of 1,25-dihydroxyvitamin D is mediated by its binding to vitamin D receptor (VDR). VDR forms a heterodimer, typically with retinoid X receptor, to regulate vitamin D target genes. We evaluated the relationship between VDR polymorphism and clinical charac- teristics associated with prostate cancer risk and prognosis among Egyptian men. Materials and methods: This case-control study included 2 groups of patients: group A, a control group of 50 subjects with benign prostate hyperplasia, and group B, 50 subjects newly diagnosed with prostate cancer. All participants performed complete blood count, liver and kidney function tests, prostate specific antigen measurement, histopathological analysis and immunohistochemistry for Dickkopf Homolog 3. Restriction fragment length polymorphism-polymerase chain reaction as performed to detect VDR polymorphism. Results: Patients with prostate cancer and controls showed a significantly different CA genotype frequency ( p = 0.007). Furthermore, prostate-specific antigen levels were significantly different in different genotypes in patients with prostate cancer ( p < 0.001). Finally, T stage and the VDR ApaI C/A polymorphism were significantly associated ( p <0.041). Conclusion: The VDR ApaI C/A polymorphism may be a diagnostic and prognostic marker for prostate cancer in Egyptian men. Keywords: Prostate cancer; Prostate-specific antigen; Vitamin D receptor polymorphism [5] 1. Introduction rearrangements. Hence, genetic variations in prostate cancer– related genes, including the vitamin D receptor gene (VDR), may be Prostate cancer is the most commonly diagnosed cancer and the [6] important in determining disease susceptibility. [1] second most common cause of death among men. Its incidence Vitamin D is involved in many functions other than bone metab- [2] is highest among Africans, followed by Whites and Mongolians, olism, including the reduction of inflammation and modulation of which may be explained by differences in social, environmental, and cellular processes such as cell growth, neuromuscular and immune genetic factors. In Egypt, prostate cancer accounts for approximately [7] functions, and glucose metabolism. Vitamin D also modulates 4.27% of all cancers based on the National Population-Based Registry Program of Egypt 2008–2011. This number is expected numerous genes encoding proteins that regulate cell proliferation, to increase because the population and average life expectancy differentiation, and apoptosis. The VDR is present in many tissues [3] are increasing in Egypt. and converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in However, the etiology of prostate cancer remains unclear. Risk [8] some of these tissues. factors for prostate cancer include aging, diet, obesity, lifestyle, eth- Measurement of the prostate-specific antigen (PSA) level is a nicity, smoking, infections, prostate gland inflammation, and va- standard test used to diagnose prostate cancer. The Food and Drug [4] sectomy. Exposure to certain chemicals and genetic predisposi- Administration approved this test in 1986 for evaluating disease tion may also be involved. In addition, oncogene activation and [9] progression. However, the specificity of PSA for diagnosing subsequent tumor development may be caused by structural genomic [10] prostate cancer is very low, and thus, more specific molecular markers are required to enable early diagnosis and treatment, *Corresponding Author: Samia Hussein, Medical Biochemistry Department, Faculty of which decrease mortality in patients with prostate cancer. Medicine, Zagazig University, Zagazig, 44511, Egypt (S. Hussein). E-mail address: shmohammed@medicine.zu.edu.eg. Prostate cell division is influenced by the steroid hormones tes- Current Urology, (2022) 16, 4, 246–255 tosterone and vitamin D, the actions of which are mediated by [11] Received February 14, 2022; Accepted April 25, 2022. the androgen receptor (AR) and VDR, respectively. Prostate ep- http://dx.doi.org/10.1097/CU9.0000000000000141 ithelial cells express multiple members of the nuclear receptor su- Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. This is perfamily that regulate cell proliferation and differentiation in the an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it prostate gland. VDR is a nuclear hormone receptor that regulates is permissible to download and share the work provided it is properly cited. The gene transcription. Although this regulation has been shown to work cannot be changed in any way or used commercially without permission [12] from the journal. be disturbed in prostate cancer, the role of the VDR in prostate 246 El-attar et al. Volume 16 Issue 4 2022 www.currurol.org All eligible patients with prostate cancer were evaluated, treated, cancer remains controversial. In the Taiwanese (Asian) population, and followed-up at the Clinical Oncology and Nuclear Medicine the frequency of any genotype and prostate cancer showed no as- [13] Department. Eligible patients were enrolled from January 2018 sociation. In contrast, other studies suggested that ApaI poly- to April 2019. Patient follow-up ended in October 2021. [14,15] morphism confers susceptibility to sporadic disease. All patients provided full histories and underwent physical examina- Based on the controversial role of VDR in prostate cancer, stud- tion and complete blood count (CBC), liver and kidney function tests, ies are needed to determine whether VDR polymorphisms are use- PSA measurement, histopathological analysis to confirm prostate cancer, ful as diagnostic and prognostic markers among Egyptian patients. and immunohistochemistry (IHC) for Dickkopf homolog 3 (DKK3). The patients underwent hormonal treatment. Biochemical re- 2. Materials and methods lapse was defined as a PSA increase of 2 ng/mL above the nadir [16] 2.1. Patients (Phoenix Criteria, 2005). According to the D'Amico risk strati- fication system, patients were classified into 3 groups to predict This prospective study was conducted in the Department of Clinical posttreatment biochemical failure. Low risk was defined as 1992 Oncology and Nuclear Medicine, Zagazig University Hospitals, and AJCC T1/T2a, PSA level ≤10 ng/mL, and Gleason score of ≤6. In- Medical Biochemistry and Molecular Biology Department, Faculty termediate risk was defined as 1992 AJCC T2b and/or PSA of 10 of Medicine, Zagazig University, Zagazig, Egypt, in collaboration to 20 ng/mL, and/or Gleason score of 7. High-risk disease was clas- with the Zoology Department, Faculty of Science, Zagazig University. sified as any one of the following high-risk features: 1992 AJCC This was a case-control study performed to evaluate 2 groups. ≥T2c, PSA >20 ng/mL, or Gleason score of 8 to 10. Group A (control group) included 50 patients with benign prostate hyperplasia. Group B included 50 patients newly diagnosed with prostate cancer as confirmed by histopathological analysis. Partici- 2.2. Immunohistochemistry pants provided written informed consent after the procedures and Immunohistochemical staining was performed using the polymer En- possible hazards were explained. The study was approved by the Insti- vision Detection System and Dako EnVision kit (Dako, Glostrup, tutional Review Board of the Faculty of Medicine, Zagazig University. Denmark). Tissue sections (3–5 μm) were deparaffinized in xylene Inclusion criteria for the patients were as follows: age of between and rehydrated in graded alcohol. The slides were incubated for 50 and 85 years, histologically confirmed adenocarcinoma of the pros- 10 minutes in 3% hydrogen peroxide to block endogenous peroxidase tate without evidence of neuroendocrine or small cell differentiation, activity, followed by treatment with Dako Target Antigen Retrieval Solu- Gleason score ≥7, any stage including low-volume metastatic disease, tion (pH 6.0). The slides were incubated with an anti-DKK3 antibody Eastern Cooperative Oncology Group performance status (ECOG (ab187532; Abcam, Cambridge, UK). The reaction was visualized PS) between 0 and 2, eligible for hormonal treatment, and adequate or- by incubating the sections with diaminobenzidine for 15 minutes. gan function. The volume of the disease as a potential predictor was in- The sections were stained with Mayer hematoxylin. Immunohisto- troduced by the chemohormonal therapy versus androgen ablation chemical scoring was performed by a pathologist using a graded randomized trial for extensive disease in prostate cancer based on im- scale from 0 to 3+, where 0 to 2 represented weak staining, 2+ to aging with a bone scan and computed tomographic scanning. 3 represented moderate staining, and 3+ represented strong staining. High-volume metastasis was defined as ≥4 bone metastases, including [14] ≥1 outside the vertebral column or pelvis and/or visceral metastasis. 2.3. Biochemical and molecular procedures Exclusion criteria included an age of <50 or >85 years, unavail- able histology, ECOG PS >2, severe concurrent illness, or comor- Random blood glucose, total bilirubin, direct bilirubin, alanine bid disease that would make the subject unsuitable for enrollment. transaminase, aspartate transaminase, albumin, urea, and creatinine Table 1 Difference in clinicopathological features between the studied groups. Mean ± SD Variables Controls (n = 50) Prostate cancer (n = 50) t test p Age, yr 68.9 ± 6.78 62.9 ± 6.33 0.27 0.76 Hemoglobin, g/dL 13.2 ± 1.45 12.1 ± 1.69 3.56 0.001* Red blood cells, cells 10 /μL 4.86 ± 0.46 4.61 ± 0.41 2.92 0.005* White blood cells, cells 10 /μL 7.04 ± 2.47 7.87 ± 2.74 1.63† 0.08 Platelets, cells 10 /μL 232.5 ± 58.3 233.6 ± 75.1 0.08 0.94 Prothrombin time, s 13.97 ± 0.66 13.9 ± 0.64 0.85 0.399 RBG, mg/dL 121.4 ± 32.1 114.5 ± 30.9 1.1 0.29 Total bilirubin, mg/dL 0.82 ± 0.12 0.87 ± 0.12 2.31 0.02* Direct bilirubin, mg/dL 0.16 ± 0.04 0.18 ± 0.04 2.63 0.01* Alanine transaminase, U/L 18.6 ± 8.82 23.4 ± 13.1 1.13† 0.08 Aspartate transaminase, U/L 21.2 ± 9.27 24.6 ± 12.6 1.37† 0.17 Albumin, g/dL 4.23 ± 0.44 4.31 ± 0.41 0.91 0.37 Creatinine, mg/dL 0.96 ± 0.19 1.01 ± 0.26 1.11 0.26 Urea, mg/dL 26.3 ± 7.14 27.5 ± 9.04 0.42 0.68 Prostate-specific antigen, ng/mL 1.86 ± 1.18 85.4 ± 34.2 8.62 <0.001 RBG = random blood glucose; SD = standard deviation. *p < 0.05 (significant). Mann-Whitney test. p < 0.001 (highly significant). 247 El-attar et al. Volume 16 Issue 4 2022 www.currurol.org Figure 1. (A) Box-plot analysis of PSA levels among patients with prostate cancer and controls. (B) Genotypes distribution of the VDR gene among patients with pros- tate cancer and controls. (C) Box-plot analysis of PSA levels in genotypes of VDR among prostate cancer cases. PSA = prostate-specific antigen; VDR = vitamin D receptor. were measured using a semiautomated chemistry analyzer (Sunostik (DFS) was calculated as the time from the date of local treatment to the Medical Technology, Changchun, China) using commercially avail- date of relapse or censored at the last follow-up visit. Overall survival able kits (Spinreact, Girona, Spain). A CBC was determined using a (OS) was calculated as the time between the date of diagnosis and date BeneSphera (Avantor, Radnor, PA). of death or final follow-up visit. DFS and OS were stratified based on the DNA was extracted from EDTA blood samples using a commer- DKK3 IHC results in malignant cells and VDR ApaI C/A polymorphism. cially available G-spin Total Genomic DNA Extraction Kit (iNtron These time-to-event distributions were estimated using Kaplan-Meier Biotechnology, Seongnam, Korea). Polymerase chain reaction (PCR) am- plots and compared using 2-sided exact log-rank tests. Statistical plification was performed using a thermal cycler (PerkinElmer, Waltham, significance was set at p < 0.05. All statistical analyses were per- MA). The 25-μL PCR sample mixtures contained 100-ng genomic DNA, formed using SPSS version 22.0 software for Windows (SPSS, Inc., 1.0μM of each primer (SBS, Beijing, China), and 12.5μLof2XTOPsim- Chicago, IL) and MedCalc Statistical Software version 18.9.1 (MedCalc plePreMIXn-Taqmastermix (Enzynomics,Daejeon,Korea).The primerse- Software bvba, Ostend, Belgium; http://www.medcalc.org; 2018). quences were as follows: F, 5′-CAGAGCATGGACAGGGAGCAA-3′ and R, 5′-GCAACTCCTCATGGCTGAGGTCTC-3′. The PCR products were 3. Results digested with the restriction enzyme ApaI (Enzymonics), and the 3.1. Clinical and biochemical characteristics of study subjects fragments were separated using 2% agarose gel electrophoresis with a 100-bp marker. The gels were stained with ethidium bro- The 2 groups did not significantly differ in terms of age (p = 0.76). There mide and visualized using a UV transilluminator. was a significant decrease in hemoglobin and red blood cell counts in pa- tients with prostate cancer compared with the controls (p = 0.001 and 2.4. Statistical analysis 0.005, respectively), whereas other CBC parameters did not significantly Continuous variables are expressed as the mean ± standard deviation differ between groups (p > 0.05). Total and direct bilirubin levels were and median (range), and categorical variables are expressed as percent- significantly increased among prostate cancer cases ( p =0.02 and ages. Variables presented as percentages were compared using the Pear- 0.01, respectively), whereas other liver and kidney function tests son χ test or Fisher exact test, when appropriate. Disease-free survival showed no significant difference between the 2 groups ( p > 0.05). Table 2 Different genotypes and allele distributions of vitamin D receptor gene among the studied groups. Group Genotype Prostate cancer (n = 50) Controls (n = 50) χ p Odds ratio (95% confidence interval) AA 26 (52%) 16 (32%) ‐‐ 1 CA 11 (22%) 30 (60%) 3.14 0.007* 0.23 (0.09–0.57) CC 13 (26%) 4 (8%) 1.06 0.29 2 (0.55–7.2) A allele 63 (63%) 62 (62%) 0.03 0.97 0.96 (0.54–1.7) C allele 37 (37%) 38 (38%) *p < 0.05 (significant). 248 El-attar et al. Volume 16 Issue 4 2022 www.currurol.org A highly significant increase in pretreatment PSA levels was ob- infolding. Tall secretory epithelial cells had a pale clear cytoplasm served among prostate cancer cases ( p < 0.001; Table 1, Fig. 1A). and uniform round or oval nuclei. In well-differentiated prostate cancer sections, the malignant glands exhibited nuclear enlargement 3.2. Vitamin D receptor gene polymorphism and hyperchromasia, prominent nucleoli, intraluminal blue mucin, and the absence of a basal cell layer. In moderately differentiated CA genotype differed significantly between patients with prostate prostate cancer, the malignant glands were arranged back-to-back cancer and controls ( p = 0.007). However, the distribution of A with little intervening stroma and cribriform patterns. Poorly differ- and C alleles did not differ between groups ( p = 0.97) (Table 2, entiated prostate cancer showed solid groups of malignant epithelial Fig. 1B). In addition, PSA levels were significantly different in the cells with nuclear enlargement and abnormal mitotic figures (Fig. 2). genotypes of group B ( p < 0.001; Table 3, Fig. 1C). However, the VDR polymorphism across the 3 D'Amico risk groups did not significantly differ ( p = 0.68; Table 3). 3.4. Relation between clinicopathological features and DKK3 IHC in malignant cells 3.3. Histopathological results High and low expression of DKK3 was detected in 30% and 70% of The benign prostatic gland showed corpora amylacea. Benign patients with prostate cancer, respectively (Fig. 3). The pretreatment glands had undulating luminal contours with tufts and papillary PSA and DKK3 IHC showed a significant association in malignant Table 3 Relation between clinicopathological features and DKK3 IHC in malignant cells/VDR ApaI genotypes in patients with prostate cancer (n = 50). DKK3 IHC in malignant cells VDR ApaI C/A polymorphism Prostate cancer patients Low (n = 35), High (n = 15), CC (n = 13), AA (n = 26), CA (n = 11), Characteristics (n = 50), n (%) n(%) n(%) p* n(%) n(%) n(%) p* Age group, yr <60 24 (48) 16 (66.7) 8 (33.3) 0.621 5 (20.8) 11 (45.8) 8 (33.3) 0.173 ≥60 26 (52) 19 (73.1) 7 (26.9) 8 (30.8) 15 (57.7) 3 (11.5) Pretreatment prostate-specific antigen, ng/mL † † <10 16 (32) 13 (81.2) 3 (18.8) 0.011 125.4 ± 27.8 64.9 ± 20.55 86.4 ± 24.4 <0.001 10–20 13 (26) 12 (92.3) 1 (7.7) >20 21 (42) 10 (47.6) 11 (52.4) ECOG PS ECOG 0 14 (28) 11 (78.6) 3 (21.4) 0.444 3 (21.4) 10 (71.4) 1 (7.1) 0.093 ECOG 1 19 (38) 14 (73.7) 5 (26.3) 8 (42.1) 7 (36.8) 4 (21.1) ECOG 2 17 (34) 10 (58.8) 7 (41.2) 2 (11.8) 9 (52.9) 6 (35.3) Gleason score Gleason 7 6 (12) 3 (50) 3 (50) 0.630 1 (16.7) 4 (66.7) 1 (16.7) 0.846 Gleason 8 23 (46) 16 (69.6) 7 (30.4) 6 (26.1) 12 (52.2) 5 (21.7) Gleason 9 15 (30) 11 (73.3) 4 (26.7) 3 (20) 8 (53.3) 4 (26.7) Gleason 10 6 (12) 5 (83.3) 1 (16.7) 3 (50) 2 (33.3) 1 (16.7) ≤7 6 (12) 3 (50) 3 (50) 0.348 1 (16.7) 4 (66.7) 1 (16.7) 0.741 >7 44 (88) 32 (72.7) 12 (27.3) 12 (27.3) 22 (50) 10 (22.7) Tumor T2 20 (40) 16 (80) 4 (20) 0.435 7 (35) 8 (40) 5 (25) 0.041 T3 20 (40) 13 (65) 7 (35) 5 (25) 14 (70) 1 (5) T4 10 (20) 6 (60) 4 (40) 1 (10) 4 (40) 5 (50) Node N0 22 (44) 19 (86.4) 3 (13.6) 0.025 7 (31.8) 9 (40.9) 6 (27.3) 0.380 N1 28 (56) 16 (57.1) 12 (42.9) 6 (21.4) 17 (60.7) 5 (17.9) Metastasis M0 39 (78) 28 (71.8) 11 (28.2) 0.713 11 (28.2) 21 (53.8) 7 (17.9) 0.413 M1 11 (22) 7 (63.6) 4 (36.4) 2 (18.2) 5 (45.5) 4 (36.4) D'Amico risk Low 2 (25) 4 (50) 2 (25) 0.68 Intermediate 6 (37.5) 8 (50) 2 (12.5) High 5 (19.2) 14 (53.8) 7 (26.9) DKK3 IHC in malignant cells Low 35 (70) 11 (31.4) 16 (45.7) 8 (22.9) 0.325 High 15 (30) 2 (13.3) 10 (66.7) 3 (20) VDR ApaI C/A polymorphism CC 13 (26) 11 (84.6) 2 (15.4) 0.325 AA 26 (52) 16 (61.5) 10 (38.5) CA 11 (22) 8 (72.7) 3 (27.3) DKK3 = Dickkopf homolog 3; ECOG PS = Eastern Cooperative Oncology Group performance status; IHC = immunohistochemistry; VDR = vitamin D receptor. Categorical variables are expressed as number (percentage). *χ Test. p < 0.05 (significant). 249 El-attar et al. Volume 16 Issue 4 2022 www.currurol.org Figure 2. (A) Benign prostate hyperplasia: contains corpora amylacea, undulating luminal contours with tufts and papillary infoldings. The tall secretory epithelial cells have a pale and clear cytoplasm and uniform round or oval nuclei (H&E, original magnification 100). (B) Well-differentiated prostate cancer: malignant glands showed nuclear enlargement and hyperchromasia, prominent nucleoli, intraluminal blue mucin, and the absence of a basal cell layer (H&E, original magnification 400). (C) Mod- erately differentiated: malignant glands are arranged back-to-back with little intervening stroma and cribriform pattern (H&E, original magnification 400). (D) Poorly dif- ferentiated prostate cancer: solid groups of malignant epithelial cells with nuclear enlargement and abnormal mitotic figures (H&E, original magnification 400). H&E = hematoxylin and eosin. cells, where 81.2% of patients with PSA <10 ng/mL exhibited low 3.5. Relation between clinicopathological features and VDR DKK3 levels versus 47.6% of patients with PSA >20 ng/mL ApaI C/A polymorphism ( p = 0.011). In addition, a significant association between the N T stage and VDR ApaI C/A polymorphism showed a significant as- stage and DKK3 IHC in malignant cells was observed; 86.4% of sociation, with 25% of patients with T2 tumors displaying a CA patients with node-negative disease had low DKK3 levels compared genotype versus 50% of patients with T4 tumors displaying this with 57.1% of patients with node-positive disease (p = 0.025; Table 3). genotype ( p = 0.041; Table 3). Figure 3. (A) Benign prostatic hyperplasia with a high cytoplasmic expression of DKK3 (IHC, original magnification 100). (B) Moderately differentiated prostate cancer with negative expression of DKK3 (IHC, original magnification 400). (C) Poorly differentiated prostate cancer with negative expression of DKK3 (IHC, original magnification 400). (D) Poorly differentiated prostate cancer with high expression of DKK3 (IHC, original magnification 400). DKK3 = Dickkopf homolog 3; IHC = immunohistochemistry. 250 El-attar et al. Volume 16 Issue 4 2022 www.currurol.org 3.6. Clinicopathological features and relapse 3.7. Clinicopathological features and mortality The mean follow-up duration was 44.22 months (range, 30–61 months). ECOG PS and mortality were significantly associated; 28.6% of Sixteen of 39 patients (41%) experienced disease relapse, and 15 patients with ECOG PS 0 died versus 58.8% of patients with patients (30%) died. Pretreatment PSA and relapse were signifi- ECOG PS 2 ( p = 0.002). Similarly, the Gleason score and mortal- cantly associated: 6.2% of patients with PSA <10 ng/mL relapsed ity showed a positive association, where 16.7% of patients with a versus 50% of patients with PSA >20 ng/mL ( p < 0.001). A signif- Gleason score of 7 died versus 73.3% of patients with a Gleason icant association was also observed between the Gleason score score of 9 ( p < 0.001). A significant association was also observed and relapse: 16.7% of patients with a Gleason score of 7 relapsed between the T stage and mortality, in which 15% of patients with versus 100% of patients with a Gleason score of 9 ( p = 0.008). T2 tumors died compared with 60% of patients with T4 tumors Furthermore, T stage and relapse were significantly associated ( p = 0.040). In addition, N stage and mortality were associated: with relapse in 5% of patients with T2 tumors versus in 100% 13.6% of patients with node-negative disease died versus 42.9% of patients with T4 tumors ( p < 0.001). Finally, the N stage and of patients with node-positive disease ( p = 0.025). Finally, the M relapse were significantly associated, where 13.6% of patients stage and mortality were significantly associated, in which with node-negative disease relapsed versus 76.6% of patients with 15.4% of patients with nonmetastatic disease died compared with node-positive disease ( p < 0.001; Table 4). 81.8% of patients with metastatic disease ( p < 0.001; Table 4). Table 4 Relation between clinicopathological features, DKK3 IHC in malignant cells, VDR ApaI C/A polymorphism, and outcomes of patients with prostate cancer (n = 50). Relapse Mortality Patients with Patients with prostate cancer Absent Present prostate cancer Alive (n = 35), Died (n = 15), Characteristics (n = 39), n (%) (n = 23) n (%) (n = 16) n (%) p* (n = 50), n (%) n(%) n(%) p* Age group, yr <60 18 (46.2) 12 (66.7) 6 (33.3) 0.366 24 (48) 16 (66.7) 8 (33.3) 0.621 ≥60 21 (53.8) 11 (52.4) 10 (47.6) 26 (52) 19 (73.1) 7 (26.9) Pretreatment prostate-specific antigen, ng/mL <10 16 (41) 15 (93.8) 1 (6.2) <0.001 16 (32) 13 (81.2) 3 (18.8) 0.468 10–20 11 (28.2) 2 (18.2) 9 (81.8) 13 (26) 8 (61.5) 5 (38.5) >20 12 (30.8) 6 (50) 6 (50) 21 (42) 14 (66.7) 7 (33.3) ECOG PS ECOG 0 14 (35.9) 9 (64.3) 5 (35.7) 0.260 14 (28) 10 (71.4) 4 (28.6) 0.002 ECOG 1 19 (48.7) 9 (47.4) 10 (52.6) 19 (38) 18 (94.7) 1 (5.3) ECOG 2 6 (15.4) 5 (83.3) 1 (16.7) 17 (34) 7 (41.2) 10 (58.8) Gleason score † † Gleason 7 6 (15.4) 5 (83.3) 1 (16.7) 0.008 6(12) 5 (83.3) 1(16.7) <0.001 Gleason 8 23 (59) 12 (52.2) 11 (47.8) 23 (46) 20 (87) 3 (13) Gleason 9 4 (10.3) 0 (0) 4 (100) 15 (30) 4 (26.7) 11 (73.3) Gleason 10 6 (15.4) 6 (100) 0 (0) 6 (12) 6 (100) 0 (0) ≤7 6 (15.4) 5 (83.3) 1 (16.7) 0.370 6 (12) 5 (83.3) 1 (16.7) 0.654 >7 33 (84.6) 18 (54.5) 15 (45.5) 44 (88) 30 (68.2) 14 (31.8) Tumor † † T2 20 (51.3) 19 (95) 1 (5) <0.001 20 (40) 17 (85) 3 (15) 0.040 T3 16 (41) 4 (25) 12 (75) 20 (40) 14 (70) 6 (30) T4 3 (7.7) 0 (0) 3 (100) 10 (20) 4 (40) 6 (60) Node † † N0 22 (56.4) 19 (86.4) 3 (13.6) <0.001 22 (44) 19 (86.4) 3 (13.6) 0.025 N1 17 (43.6) 4 (23.5) 13 (76.5) 28 (56) 16 (57.1) 12 (42.9) Metastasis M0 39 (78) 33 (84.6) 6 (15.4) <0.001 M1 11 (22) 2 (18.2) 9 (81.8) DKK3 IHC in malignant cells Low 28 (71.8) 18 (64.3) 10 (35.7) 0.307 35 (70) 23 (65.7) 12 (34.3) 0.502 High 11 (28.2) 5 (45.5) 6 (54.5) 15 (30) 12 (80) 3 (20) VDR ApaI C/A polymorphism CC 11 (28.2) 7 (63.6) 4 (36.4) 0.193 13 (26) 12 (92.3) 1 (7.7) 0.082 AA 21 (53.8) 10 (47.6) 11 (52.4) 26 (52) 15 (57.7) 11 (42.3) CA 7 (17.9) 6 (85.7) 1 (14.3) 11 (22) 8 (72.7) 3 (27.3) DKK3 = Dickkopf homolog 3; ECOG PS = Eastern Cooperative Oncology Group performance status; IHC = immunohistochemistry; VDR = vitamin D receptor. Categorical variables are expressed as number (percentage). *χ Test. p < 0.05 (significant). 251 El-attar et al. Volume 16 Issue 4 2022 www.currurol.org Table 5 Relation between treatment and outcomes of patients with prostate cancer (n = 50). Relapse Mortality Patients with Patients with prostate cancer Absent Present prostate cancer Alive (n = 35), Died (n = 15), Treatment (n = 39), n (%) (n = 23), n (%) (n = 16), n (%) p* (n = 50), n (%) n(%) n(%) p* Local radiotherapy No 1 (2.6) 0 (0) 1 (100) 0.410 12 (24) 2 (16.7) 10 (83.3) <0.001† Yes 38 (97.4) 23 (60.5) 15 (39.5) 38 (76) 33 (86.8) 5 (13.2) Hormonal deprivation LHRH 15 (38.5) 12 (80) 3 (20) 0.035† 15 (30) 12 (80) 3 (20) 0.502 LHRH + AR blockers 24 (61.5) 11 (45.8) 13 (54.2) 35 (70) 23 (65.7) 12 (34.3) Neoadjuvant hormonal No 38 (97.4) 23 (60.5) 15 (39.5) 0.410 38 (76) 33 (86.8) 5 (13.2) <0.001† Yes 1 (2.6) 0 (0) 1 (100) 12 (24) 2 (16.7) 10 (83.3) Concurrent hormonal No 7 (17.9) 6 (85.7) 1 (14.3) 0.206 18 (36) 8 (44.4) 10 (55.6) 0.003† Yes 32 (82.1) 17 (53.1) 15 (46.9) 32 (64) 27 (84.4) 5 (15.6) Posttreatment prostate-specific antigen, ng/mL ≤0.5 28 (71.8) 18 (64.3) 10 (35.7) 0.307 34 (68) 24 (70.6) 10 (29.4) 1.000 >0.5 11 (28.2) 5 (45.5) 6 (54.5) 16 (32) 11 (68.8) 5 (31.2) Relapse (n = 39) (n = 33) (n = 6) Absent 23 (59) 21 (91.3) 2 (8.7) 0.205 Present 16 (41) 12 (75) 4 (25) AR = androgen receptor; LHRH = luteinizing hormone-releasing hormone. Categorical variables are expressed as number (percentage). *χ Test. †p < 0.05 (significant). Figure 4. Kaplan-Meier plot: Disease-free survival. (A) All prostate cancer patients. (B) Stratified by DKK3 IHC in malignant cells. (C) Stratified by VDR ApaI C/A poly- morphism. DKK3 = Dickkopf homolog 3; IHC = immunohistochemistry; VDR = vitamin D receptor. 252 El-attar et al. Volume 16 Issue 4 2022 www.currurol.org 3.8. Relation between treatment and relapse were 62.3% and 36.4%, respectively. The 4-year DFS values among patients with the CA, CC, and AA genotypes were Thirty-eight patients (76%) underwent local radiotherapy. Thirty-five 83.3%, 63.6%, and 42.8%, respectively (Fig. 4). patients (70%) were administered a combined androgen blockade (luteinizing hormone-releasing hormone [LHRH] + AR blockers). 3.11. Kaplan-Meier plot for OS The mean duration of hormonal treatment was 38.14 months The 5-year OS among the 50 group B patients was 28.6%. The (range, 28–56 months). Twelve patients (24%) were administered 4-year OS values among patients with low and high DKK3 expres- neoadjuvant hormonal therapy, and 32 patients (64%) were admin- sion were 67.6% and 71.8%, respectively. In addition, the 4-year istered concurrent hormonal treatment. Sixteen patients (32%) OS values among patients with the CA, CC, and AA genotypes showed posttreatment PSA >0.5 ng/mL. A significant association were 70%, 91.7%, and 53.3%, respectively (Fig. 5). was observed between hormonal deprivation and relapse, as 20% of patients treated with LHRH relapsed versus 54.2% of patients treated with LHRH + AR blockers relapsed ( p = 0.035; Table 5). 4. Discussion In addition to its role in calcium homeostasis, vitamin D affects cell 3.9. Relation between treatment and mortality growth and differentiation, and immune function, and can protect Local radiotherapy was positively associated with mortality: against cardiovascular disease, infections, cancer, and autoimmune 83.3% of untreated patients died versus 13.2% of treated patients [8] diseases. Prostatic epithelial cells express VDR and 1α-hydroxylase ( p < 0.001). In contrast, neoadjuvant hormonal treatment was as- [14] enzymes that are required for the synthesis and action of calcitriol. sociated with higher mortality: 13.2% of untreated patients died In prostate cancer, various genes function together with individual versus 83.3% of treated patients ( p < 0.001). In addition, concur- and environmental factors to affect the development and prognosis of [17] rent hormonal treatment and mortality were positively associated; prostate cancer. Thus, identifying genetic risk factors is essential for 55.6% of untreated patients died versus 15.6% of treated patients early disease detection. Single-nucleotide polymorphisms may con- ( p = 0.003; Table 5). tribute to the pathogenesis of prostate cancer. Ethnic and geographic variations in the incidence and mortality of prostate cancer may result 3.10. Kaplan-Meier plot for DFS from polymorphisms in genes associated with androgen secretion and [18] metabolism. The 4-year DFS among group B patients was 55.8%. The 4-year The association of VDR polymorphisms with the risk DFS values among patients with low and high DKK3 expression of prostate cancer among different ethnic groups suggests that these Figure 5. Kaplan-Meier plot: Overall survival. (A) Stratified by DKK3 IHC in malignant cells. (B) Stratified by VDR ApaI C/A polymorphism. (C) All patients with prostate cancer. DKK3 = Dickkopf homolog 3; IHC = immunohistochemistry; VDR = vitamin D receptor. 253 El-attar et al. Volume 16 Issue 4 2022 www.currurol.org [19] [26,29] polymorphisms can be used as risk markers for the disease. VDR is with prostate cancer risk in 2 meta-analyses. However, [30] highly polymorphic, and its allele frequencies are highly variable Habuchi et al. observed a significant difference between pa- [20] [31] among different races and ethnic groups. tients with prostate cancer and female controls, and Cicek et al. Age is a well-established risk factor for prostate cancer, with an found an association between ApaI polymorphism and prostate increased risk after 50 years of age; approximately 6 in 10 men cancer. [19] 65 years and older present with the disease. In this study, the We found a significant association between the T stage and 2 groups of men were age-matched. VDR ApaI C/A polymorphism. However, no significant difference We observed a significant increase in total and direct bilirubin was found between genotypes regarding tumor differentiation, levels among patients with prostate cancer compared with those grade, Glasson score, or DKK3 expression. Similar to our results, [32] [15] in controls. Causes of hyperbilirubinemia in patients with prostate Suzuki et al. and Onen et al. observed no relationship be- cancer include obstruction of the bile duct by the primary tumor, tween clinicopathological parameters (tumor stage, Gleason score, pressure effect of enlarged lymph nodes, or infiltration of the PSA levels) and the genotype distributions of ApaI. Moreover, [21] [25] liver. Paraneoplastic cholestasis may also be responsible for Zhang and Shan found no specific relationship between ApaI the direct effect of the primary tumor or metastasis. However, polymorphism and prostate cancer TNM stage or Gleason score these features are extremely rare in patients with prostate in either a dominant or recessive model. This discrepancy may be [22] cancer. Because we excluded high-volume metastasis from our explained by ethnic variations and the different sample sizes. study, visceral liver involvement was excluded, and thus, one pos- sible explanation for our results is the enlarged lymph node effect. 5. Conclusions We found a highly significant increase in PSA levels among pa- VDR ApaI polymorphism may play a role in the development and tients with prostate cancer compared with those in controls progression of prostate cancer. ApaI polymorphism may help iden- ( p < 0.001). An increase was observed in patient PSA levels among tify individuals at high risk of prostate cancer and select suitable CC and CA genotypes compared with in AA genotype. Similarly, [19] treatment strategies. Because of the significant association between Nunes et al. reported a significant association between VDR VDR ApaI polymorphism and both PSA levels and tumor stage, polymorphisms and PSA levels. PSA expression is controlled by an- VDR ApaI polymorphism shows potential as a prognostic marker drogens via the AR. A link between VDR and AR has been sug- for prostate cancer in Egyptian men. gested because prostate cells intensively respond to dihydrotestos- [23] The outcomes of prostate cancer can be affected by several terone in the presence of calcitriol. Furthermore, both exhibit factors other than VDR polymorphism. We could not reduce selec- synergistic interactions that regulate prostate cell proliferation tion bias through matched comparison/analysis or subgroup anal- and PSA secretion. Moreover, VDR polymorphisms associated ysis because of the relatively small sample size. Screening for asso- with PSA levels may be useful prognostic factors. PSA concentra- ciations between genetic variants and prostate cancer prognosis tions >10 ng/mL were significantly associated with an increased requires a large sample size and long-term follow-up. Further risk of recurrence. In addition, PSA levels >2 ng/mL during the year large-scale case-control and cohort populations of different races before diagnosis increased the risk of mortality, despite treatment [24] and ethnicities with more polymorphic sites are required to con- with radical prostatectomy. firm the association between VDR polymorphisms and prostate ApaI polymorphism is in intron 8 of the 3′ untranslated region, a cancer development and progression. noncoding region; however, this polymorphism has not been shown to affect splicing or transcription factor binding sites and thus does not affect the quantity, structure, or function of VDR protein. There- Acknowledgments fore, the polymorphism seems to be silent. However, it influences None. VDR expression and function, particularly messenger RNA stability and gene transcription. This effect of this polymorphism may be linked to other genetic variations in VDR itself or nearby polymor- Statement of ethics phic genes and may alter the ability of VDR protein to bind calcitriol The study was approved by the Institutional Review Board of the or activate vitamin D response element. This influence may alter the Faculty of Medicine, Zagazig University (ZU-IRB#9237/5-1- expression of regulatory genes, such as that of cyclin-dependent ki- [20,14] 2022). Participants provided written informed consent after the nases, that control cell division in the prostate. procedures, and possible hazards were explained. All procedures We observed a significant difference in genotype between patients performed in this study involving human participants were in ac- with prostate cancer and controls (p < 0.001). Moreover, the CA geno- cordance with the ethical standards of the institutional and na- type was significantly more common in the control group than in the tional research committee and with the 1964 Helsinki Declaration prostate cancer group (p = 0.007), but the distribution of A and C al- [14] and its later amendments or comparable ethical standards. leles did not differ between groups (p = 0.97). Kambale et al. found similar results and suggested that the CA genotype exerts a protective [15] effect, as it is less responsive to cell proliferation. Similarly, Onen et al. Conflict of interest statement found that VDR ApaI polymorphism may confer susceptibility to No conflict of interest has been declared by the authors. sporadic prostate cancer in the Turkish (White) population and demonstrated a relationship between C allele carrier of ApaI poly- morphism and sporadic prostate cancer. Other studies revealed no Funding source association between the frequency of any genotype and prostate [13,19,25,26] None. cancer. No differences in ApaI VDR polymorphisms and prostate can- [27] [28] cer predisposition were found in White, African American, Data availability statement [13] and Asian populations between cases and controls. Further- more, VDR ApaI polymorphism was not significantly correlated Data are available upon a reasonable request. 254 El-attar et al. Volume 16 Issue 4 2022 www.currurol.org Author contributions Phoenix Consensus Conference. Int J Radiat OncolBiolPhys 2006;65(4): 965–974. AA, AZE-a, SH: Conception; [17] Hsing AW, Reichardt JK, Stanczyk FZ. Hormones and prostate cancer: AA,SH,SA,MKE,HMI,MH,AZ-a:Interpretationoranalysisofdata; Current perspectives and future directions. Prostate 2002;52(3):213–235. [18] Cancel-Tassin G, Cussenot O. Genetic susceptibility to prostate cancer. SH: Preparation of the manuscript; BJU Int 2005;96(9):1380–1385. 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Current Urology – Wolters Kluwer Health
Published: Dec 16, 2022
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