Polymorphisms in the gene encoding CYP1A2 influence prostate cancer risk and progression.

The role of the cytochrome P450 1A2 (CYP1A2) rs2472299, rs2470890 and rs11072508 polymorphisms in prostate cancer risk, disease progression and tumour development remains unclear. The potential associations of these three CYP1A2 polymorphisms and haplotypes with prostate cancer susceptibility and its clinicopathological characteristics were therefore investigated. The present case-control study consisted of 522 patients with prostate cancer and 554 healthy controls. High-resolution melting analysis was used to determine the CYP1A2 polymorphisms. No significant association in prostate cancer risk was seen for CYP1A2 rs2472299 and rs11072508. However, a significantly decreased risk of prostate cancer was found for CYP1A2 rs2470890 [odds ratio (OR), 0.67; P=0.02] in the recessive model. After analysis of the associations of clinical status and these three CYP1A2 polymorphisms, the CYP1A2 rs2470890 and rs11072508 polymorphisms showed a positive association with a higher Gleason score (rs2470890 OR, 1.36, P=0.04 in the allelic model; rs11072508 OR, 1.37, P=0.04 in the allelic model and OR, 1.60, P=0.03 in the dominant model). All three polymorphisms showed a significant positive association with pathological T stage in the additive, allelic and dominant genetic models (P<0.05). Haplotype analysis revealed that the most common haplotypes 'GTT' and 'ACC' were significantly associated with pathological T stages 3 and 4 (OR, 0.62; P=0.02 and OR, 1.54; P=0.03, respectively). A significant association was found between the 'GTT' haplotype and the Gleason score (OR, 0.71; P=0.03). In conclusion, these CYP1A2 polymorphisms and haplotypes have the potential to predict prostate cancer disease progression.

The driving power of the cell cycle: cyclin-dependent kinases, cyclins and their inhibitors.

The cell cycle covers cell proliferation and growth and is strictly regulated by cyclin-dependent kinase, cyclins and their inhibitors. Cyclin-dependent kinases are serine/threonine kinases that are activated in certain phases of the cell cycle by regulatory subunits, cyclins, with which they form functional heterodimeric complexes. Under physiological conditions, the activation of cyclin-dependent kinases and cyclins is strictly controlled. The formation of these complexes is inhibited, as needed, either specifically or non-specifically, by cyclin-dependent kinase inhibitors. Progression through the cell cycle is a critical process that drives many aspects of cellular function. The cell cycle is a series of events that occurs in a repeating pattern. Each cell cycle consists of two phases, interphase and mitotic phase. Their dysregulation leads to disruption of cell cycle coordination and uncontrollable cell proliferation, which is the main feature of tumorigenesis (Fig. 1, Ref. 69). Keywords: cell cycle, regulation, cyclin­dependent kinases, cyclins, inhibitors.

Competition for soil resources forces a trade-off between enhancing tree productivity and understorey species richness in managed beech forests.

Traditionally focussed on maximising productivity, forest management increasingly has to consider other functions performed by the forest stands, such as biodiversity conservation. Terrestrial plant communities typically possess a hump-back relationship between biomass productivity and plant species richness. However, there is evidence of a reverse relationship in forests dominated by beech, one of the most competitive and widespread tree species in temperate Europe. To fully explore the tree productivity-species richness relationship, we investigated above- and below-ground drivers of understorey plant species richness. We focussed on managed beech forests growing along an elevation gradient in Central Europe. We found that the lowest understorey plant diversity was under conditions optimal for beech. Tree fine root mass, canopy openness, soil C/N ratio, the interaction between tree fine root mass and stoniness, and stand structural diversity explain the variation of understorey species richness. We show that the competition for soil resources is the main driver of plant species diversity in managed forests; maximising beech growth in optimal conditions may thus come at the expense of understorey plant richness.

The ubiquitous expression of pyruvate carboxylase among human prostate tumors.

Pyruvate carboxylase (PC) is a mitochondrial enzyme catalyzing the ATP-dependent reaction of pyruvate prolongation with bicarbonate ion to oxaloacetate. The synthesis of oxaloacetate by PC, an intermediate of the Krebs cycle, is recently recognized as a significant anaplerotic reaction that supports the biosynthetic capability, growth, aggressiveness, and even viability of several cancer cell types. PC expression was confirmed in several types of cancer cells and tumors. To evaluate the possibility that prostate tumor-forming cells are also exploiting the anaplerotic role of PC, we applied immunoblotting analysis to estimate its presence. Our results revealed that PC is present among the lysate proteins derived from prostate cancer and benign prostatic hyperplasia samples. The expression of PC in cells of prostate tumors and benign prostatic hyperplasia supposes that PC could facilitate the formation of oxaloacetate in situ and enhance the autonomy of their biosynthetic metabolism from the availability of extracellular substrates by increasing the cellular anaplerotic capability (Tab. 1, Fig. 1, Ref. 30). Keywords: pyruvate carboxylase, prostate cancer, cancer metabolism, anaplerosis.

Role of Genetic Variations in CDK2, CCNE1 and p27KIP1 in Prostate Cancer.

BACKGROUND/AIM: Our aim was to investigate possible influences of genetic variants in genes involved in the G1/S transition [cyclin-dependent kinase-2 (CDK2), cyclin E1 (CCNE1) and cyclin-dependent kinase inhibitor 1B (p27KIP1)] on the expression/activity of their corresponding proteins and to assess the functional impact of these variants on the risk of prostate cancer. MATERIALS AND METHODS: We genotyped 530 cases and 562 healthy controls for two relevant single nucleotide polymorphisms (CDK2 rs2069408 and CCNE1 rs997669) by TaqMan genotyping assay. p27KIP1 rs2066827 polymorphisms were studied by polymerase chain reaction-restriction fragment length polymorphism assay. In addition, the expression of CDK2, CCNE1 and p27KIP1 was evaluated by quantitative real-time-polymerase chain reaction and western blotting in 44 prostate cancer tissues and 31 benign prostatic hyperplasia tissues. RESULTS: No association was found between CDK2 rs2069408, CCNE1 rs997669 or p27KIP1 rs2066827 polymorphisms and an increased risk of prostate cancer development. Higher CDK2 expression was more prevalent in those with rs2069408 GG genotype than in AA carriers (p>0.05). We also noted reduced p27KIP1 protein expression in those with the p27KIP1 G109 allele. No difference was observed for CCNE1 expression in relation to the risky genotype (CC). A significant association was detected between CCNE1 mRNA overexpression and development of higher-grade carcinomas (Gleason score >7, p<0.05). CONCLUSION: Polymorphisms CDK2 rs2069408, CCNE1 rs997669 and p27KIP1 rs2066827 have no significant impact on prostate cancer risk nor on the gene and protein expression of CDK2, CCNE1 and p27KIP1, although high CCNE1 expression was significantly associated with a higher tumour grade in patients with prostate cancer.

Screening for the Key Proteins Associated with Rete Testis Invasion in Clinical Stage I Seminoma via Label-Free Quantitative Mass Spectrometry.

Rete testis invasion (RTI) is an unfavourable prognostic factor for the risk of relapse in clinical stage I (CS I) seminoma patients. Notably, no evidence of difference in the proteome of RTI-positive vs. -negative CS I seminomas has been reported yet. Here, a quantitative proteomic approach was used to investigate RTI-associated proteins. 64 proteins were differentially expressed in RTI-positive compared to -negative CS I seminomas. Of them, 14-3-3γ, ezrin, filamin A, Parkinsonism-associated deglycase 7 (PARK7), vimentin and vinculin, were validated in CS I seminoma patient cohort. As shown by multivariate analysis controlling for clinical confounders, PARK7 and filamin A expression lowered the risk of RTI, while 14-3-3γ expression increased it. Therefore, we suggest that in real clinical biopsy specimens, the expression level of these proteins may reflect prognosis in CS I seminoma patients.

Association between estrogen receptor ß polymorphisms and prostate cancer in a Slovak population.

Sex steroid hormones have important roles in the function of the prostate; however, they may also serve as factors in the initiation and progression of carcinogenesis. Estrogens, acting through estrogen receptors, may significantly affect prostate cancer development and progression. The main aim of the present study was to analyze the association between the rs3020449, rs4986938 and rs1256049 polymorphisms in the promoter region of the estrogen receptor ß (ESR2) gene and prostate cancer risk in the Slovak population. A total of 510 patients with prostate cancer and 184 healthy men were included in the present study. No association between the rs4986938 and rs1256049 polymorphisms and prostate cancer development and progression was revealed; however, there was a statistically significant association between the rs3020449 GG genotype [odds ratio (OR), 2.35; P=0.002] and the G allele (OR, 1.42; P=0.005) and a higher risk of prostate cancer development. The rs3020449 GG genotype was significantly associated with a higher risk of development of carcinoma with a Gleason score >7 (OR, 2.66; P=0.005), as well as with the development of carcinoma with pT3/pT4 (OR, 2.28; P=0.02). According to the results from the present study, the rs3020449 polymorphism, in the promoter region of ESR2, may be considered to have a role in the development and progression of prostate cancer in the Slovak population.

Differential profiling of prostate tumors versus benign prostatic tissues by using a 2DE-MALDI-TOF-based proteomic approach.

Oncoproteomic technologies offer a complementary approach to the understanding of cancer proteins' function and the translation of molecular knowledge into clinical practice. Our aim was to compare the proteomic profiles of prostate tumors versus benign prostatic hyperplasia (BPH) tissues in order to identify modulated proteins as the potential biomarkers for prostate cancer. Proteins extracted from twenty prostate cancer tissue specimens and ten BPH tissues were analyzed by two-dimensional electrophoresis (2-DE) coupled with MALDI-TOF mass spectrometry. Western blot and quantitative real-time PCR (RT-PCR) were performed to confirm the different amounts of protein biomarkers revealed by 2DE combined with MALDI mass spectrometry. We found 42 spots whose expression in the prostate was altered more than 1.5-fold compared with BPH tissue (p<0.05). These spots represented ten different proteins that were identified by a database search after mass spectrometry: they comprised proteins involved in the regulation of actin dynamics, the cytoskeleton, and cell motility (ACTG2, ACTA2, TPM1, DES, VIM, FLNA, and TAGLN), heat shock protein-27 (Hsp27), and proteins with other functions (TR and RANBP3). Subsequent western blot and RT-PCR assays for DES, VIM, TAGLN, and Hsp27 in prostate tumor tissues and BPH tissues confirmed the observations obtained by proteomic analysis. The cytoskeletal and cytoskeleton-associated proteins identified by this approach might be useful molecular targets for prostate cancer diagnostics and may contribute to novel therapies for prostate cancer.

Association of MDM2 T309G (rs2279744) Polymorphism and Expression Changes With Risk of Prostate Cancer in the Slovak Population.

BACKGROUND/AIM: The aim of this study was to evaluate the relationship between MDM2 T309G polymorphism and prostate cancer risk in the Slovak population and the association of this polymorphism with MDM2 expression and clinicopathological features. MATERIALS AND METHODS: The MDM2 T309G polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 506 prostate cancer patients and 592 controls. Quantitative real-time (RT)-PCR and western blot analysis were applied to examine MDM2 expression in 47 prostate cancer tissues and 43 benign prostatic hyperplasia (BPH) tissues. RESULTS: A decreased risk of prostate cancer in men carrying the GG genotype in comparison with the TT genotype was found. A decrease in the relative MDM2 mRNA and protein levels was found in prostate cancer tissues among patients with the MDM2 GG genotype. CONCLUSION: There is a potentially protective effect of the MDM2 GG genotype on the risk of prostate cancer in the Slovak male population.

Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer.

BACKGROUND/AIM: The aim of this study was to analyse the genetic profiles of metastatic castration-resistant prostate cancer (mCRPC) by using next generation sequencing to identify variants with pathogenic potential in nine DNA repair genes - BRCA1, BRCA2, RAD50, RAD51, RAD51C/D, ATM and ATR. MATERIALS AND METHODS: Isolated genomic DNA from peripheral blood of 50 patients with mCRPC was used for the sequencing of 111 genes associated with hereditary cancer on an Illumina platform. Identified variants were tested in Integrative Genomic Viewer, their clinical significance confirmed in databases and their potential impact on protein function predicted by in silico tools. RESULTS: From nine analysed DNA repair genes, we identified 14 relevant variants; three pathogenic variants - BRCA2 (rs80359306), RAD50 (rs786201531) and ATM (rs1555099760), and eleven other variants with pathogenic potential. CONCLUSION: The pathogenic variants identified in this study are located in evolutionarily conserved regions of proteins and are highly likely to affect DNA repair efficiency.

Associations Between Gene Polymorphisms of Vascular Endothelial Growth Factor and Prostate Cancer.

BACKGROUND/AIM: The aim of this study was to evaluate the association between selected polymorphisms of the vascular endothelial growth factor gene (rs699947, rs144854329, rs833061, rs2010963, rs3025039) and the risk of prostate cancer development and progression. MATERIALS AND METHODS: The present study included 446 patients with prostate cancer and 241 healthy men. Genotyping was performed by polymerase-chain reaction-restriction fragment length polymorphism analysis. RESULTS: No significant association between the individual polymorphisms studied and the risk of prostate cancer development was detected. A statistically significantly increased risk of prostate cancer development associated with the presence of 9 or 10 risky alleles was found considering the whole group of patients, as well as in patients with low-grade carcinomas (Gleason score <7). CONCLUSION: Individual polymorphisms of VEGF do not appear to contribute to prostate cancer. However, a combination of risky alleles of the studied polymorphisms significantly increases the risk of prostate cancer in Slovak patients.

Involvement of calcium regulating ion channels in contractility of human isolated urinary bladder.

This study specified the role of several key calcium-operating ion channels in contraction/relaxation of human detrusor muscle as possible target for overactive bladder (OAB) treatment. Detrusor samples, obtained from 18 males (average age 61.5 ± 5.9 years), were investigated by organ tissue bath method with following agents: diltiazem for L-type voltage-gated calcium channels; 3-fluropyridine-4-carboxylic acid (FPCA) for Orai-STIM channels; SKF 96365-hydrochloride for transient receptor potential (TRP) channels, T-type channels and Orai-STIM channels; 2- aminoethoxydiphenyl borate (2-APB) for inositol-triphosphate receptors (IP3Rs) and Orai-STIM channels. Oxybutynin and mirabegron were tested under the same conditions as controls. Mirabegron, 2-APB and FPCA exhibited the best suppressive effect on carbachol-induced detrusor contractility. As expressed by area under the contractile curve (AUCC), 2-APB, FPCA and mirabegron have similar AUCC: 1.79, 1.73, 1.73. The highest AUCC was 3.64 for diltiazem+SKF, followed by 3.21 for diltiazem, 3.16 for SKF and 2.94 for oxybutynin. The lowest median amplitude and contraction variability is for 2-APB followed by mirabegron and FPCA. There were significant differences between: 2-APB/FPCA vs.: ditiazem, diltiazem+SKF and SKF. Summary of results suggested the principal role of IP3Rs, Orai-STIM coupling and large-conductance calcium-activated potassium channels in detrusor contraction and pointed on Orai-STIM channels as possible targets for OAB pharmacotherapy.

The Role of Interleukin-6 Polymorphism (rs1800795) in Prostate Cancer Development and Progression.

BACKGROUND/AIM: Interleukin-6 is an important modulator of inflammation, which is one of the factors involved in prostate cancer. The aim of the study was to evaluate the possible association of the IL-6 -174 polymorphism (rs1800795) with the risk of prostate cancer development and progression. MATERIALS AND METHODS: The study population consisted of 446 prostate cancer patients, 377 benign prostatic hyperplasia (BHP) patients and 276 healthy men. Genotyping was performed by PCR-RFLP analysis. IL-6 plasma levels were measured by the ELISA method. RESULTS: The GC genotype (OR=0.61, p=0.005) and C allele (OR=0.8, p=0.04) of the IL-6 -174 polymorphism were significantly associated with prostate cancer. No genotype was associated with BHP. IL-6 plasma levels were significantly increased in prostate cancer patients compared to both healthy men (p=0.02) and BHP patients (p=0.008). No significant differences were observed in IL-6 plasma levels in connection with IL-6 -174 genotypes. CONCLUSION: The IL-6 -174 polymorphism was significantly associated with prostate cancer in Slovak patients.

Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial.

BACKGROUND: In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment. OBJECTIVE: To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection. DESIGN, SETTING, AND PARTICIPANTS: Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics. RESULTS AND LIMITATIONS: During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non-treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up. CONCLUSIONS: Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns. PATIENT SUMMARY: Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.

The long-term outcomes of radical prostatectomy for very high-risk prostate cancer pT3b-T4 N0-1 on definitive histopathology.

INTRODUCTION: The study aimed to assess long-term outcomes in patients with very high-risk prostate cancer (PCa) - pT3b-T4 N0-1 using the definitive histopathology following radical retropubic prostatectomy (RRP). MATERIAL AND METHODS: We have analyzed 114 patients with very high-risk PCa who underwent RRP between 1995 and 2012. Biochemical and clinical progression-free survival (BPFS, CPFS), cancer-specific and overall survival (CSS, OS) curves were constructed according to the Kaplan-Meier method. Univariate and multivariate Cox regression analysis was utilized to determine predictability of clinical and pathological parameters. RESULTS: At the 5 and 10 year mark, the BPFS was 71.3% and 35%, respectively; the CPFS was 86.8% and 69.2%, respectively; the CSS was 98% and 76.3%, respectively and the OS was 90.3% and 62.4%, respectively. Sixteen patients (14%) had lymph-node involvement. Positive surgical margins were present in 64 (56.1%) patients. Neo-adjuvant androgen deprivation therapy (ADT) was received by 22 (19.3%) patients. Adjuvant ADT alone or in combination with external radiotherapy was received by 59 (51.8%) patients. No adjuvant treatment was needed in 29 (25.4%) patients. In univariate and multivariate analysis, neo-adjuvant ADT was associated with an increased risk of BPFS and CPFS. CONCLUSIONS: Therapy applied in patients with very high-risk PCa was multimodal in most cases, with RP usually being the first step. The study confirmed that very high-risk PCa is a heterogeneous disease. A significant subset of patients remain without adjuvant therapy treatment.

Testosterone as a prospective predictor of pathological Gleason score and pathological stage in prostate cancer.

The aim of the study was to assess the relationship between preoperative circulating levels of total serum testosterone and pathological Gleason score and pathological stage in prostate cancer patients who underwent radical retropubic prostatectomy. The levels of total serum testosterone were measured in the morning just before surgery in a group of 201 prostate cancer patients. Multinomial logistic regression models were used to model the association between total preoperative testosterone (individually or in combination with other preoperative predictors such as age, PSA, clinical stage and biopsy Gleason score) and pathological Gleason score, pathological stage in prostate cancer patients. The association between age and total testosterone was modelled by robust regression. The total serum testosterone, in combination with other prognostic factors (age, PSA, clinical stage and biopsy Gleason score) in models, was not statistically significant predictor of pathological Gleason score and pathological stage. The highly significant relationship between age and preoperative total testosterone was observed (p = 0). In prostate cancer patients, the level of total serum testosterone increased with age. In conclusion, total testosterone is not a statistically significant predictive factor for pathological Gleason score and pathological stage.

Association of p53 and p21 polymorphisms with prostate cancer.

Cell cycle deregulation is common in human cancer. Alterations of the tumor-suppressor gene p53 and its downstream effector p21 have been indicated in the development of numerous human malignancies. Therefore, we hypothesize that the p53 codon 72 polymorphism, either on its own or in combination with p21 (C98A and C70T) polymorphisms, modifies the risk of prostate cancer within the Slovak population, and no previous studies have investigated these gene-gene interactions in the pathogenesis of prostate cancer in the Slovak population. Polymerase chain reaction-restriction fragment length polymorphism was used to determine the p53 and p21 genotypes in subjects comprising 300 prostate cancer patients and 446 healthy individuals. These 3 polymorphisms individually did not correlate with the prostate cancer risk. Conversely, the interaction between the p53 and p21 polymorphisms significantly decreased the risk of prostate cancer, with the odds ratio (OR) being 0.49 [95% confidence interval (CI), 0.27-0.86; P<0.05] for subjects carrying the p53 codon 72 arginine (Arg)/proline (Pro)+Pro/Pro and p21 C98A CA genotypes compared to the combined reference genotypes p53 codon 72 Arg/Arg and p21 C98A CC. Neither the p53 genotypes nor the p21 genotypes showed statistically significant differences in Gleason score or serum prostate-specific antigen levels (P>0.05). A decreased risk of prostate cancer association with the p21 C98A CA genotype (OR=0.58; 95% CI, 0.36-0.93; P<0.05) in non-smokers compared to the non-smokers with the p21 C98A CC genotype was observed. Smokers carrying the p53 codon 72 Pro/Pro genotype were not at any significant risk of prostate cancer (OR=2.97; 95% CI, 0.51-17.15) compared to the non-smokers with the Arg/Arg genotype. Taken together, to the best of our knowledge this is the first study to show that a combination of the variant genotypes of p53 codon 72 and p21 C98A may modify the prostate cancer risk within the Slovak population.

Estrogen receptor alpha polymorphisms and the risk of prostate cancer development.

PURPOSE: The main purpose of the study was to evaluate the effect of two polymorphisms in the estrogen receptor alpha, rs2077647 and rs3798577, on the development of prostate cancer, their correlation with selected clinical characteristics, as well as consideration of potential interactions between four estrogen receptor alpha polymorphisms (rs2077647, rs3798577, PvuII, XbaI). METHODS: The study was performed using 395 patients with histologically verified prostate cancer and 253 healthy male controls. RESULTS: The CC genotype of rs2077647 was significantly associated with prostate cancer (OR = 1.61). No association was found between rs3798577 polymorphism and prostate cancer. After stratification of patients according to the age at diagnosis and Gleason score, we observed significant correlation between rs2077647 polymorphism and prostate cancer risk in patients diagnosed before the age of 60 as well as patients with Gleason score <7, while rs3798577 was significantly associated with prostate cancer risk development in patients older than 60 and with Gleason score ≥7. Double analysis of each combination of four studied polymorphisms showed that presence of at least three variant alleles was associated with prostate cancer risk in all combinations, while each containing rs3798577 was significantly associated with development of high-grade carcinomas. CONCLUSIONS: The present study suggests that rs2077647 polymorphism may be a risk factor for prostate cancer especially in patients diagnosed before the age of 60, while rs3798577 polymorphism could probably serve rather as promoting factor in combination with other polymorphisms in estrogen receptor alpha contributing preferably to development of high-grade carcinomas.

Polymorphism of the SRD5A2 gene and the risk of prostate cancer.

Androgens are actively involved in the development of the prostate gland and appear to be essential for prostate carcinogenesis. The product of the SRD5A2 gene, membrane­bound steroid 5­α­reductase, type II enzyme, is key in testosterone metabolism. The present study explored the association between the SRD5A2 V89L gene polymorphism and the risk of developing prostate cancer. The study cohort consisted of 456 male Slovak patients, including 260 cases with histologically confirmed prostate cancer and 196 age­matched controls without any clinically suspected infections of the prostate. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect the SRD5A2 polymorphism on codon 89. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) for different allele variants were calculated in order to determine the association between the SRD5A2 V89L gene polymorphism and prostate cancer. The distribution of V89L variants in the control group was consistent with the Hardy­Weinberg equilibrium (χ2 test, P=0.266) with a significant deviation in the case group (χ2 test, P=0.04). However, no association between the SRD5A2 polymorphism and an increased risk of developing prostate cancer was identified. When the wild type VV variant was used as a reference, the ORs for different allele variants ranged from 1.11 (95% CI 0.66­1.87, P=0.70) for the LL genotype to 0.99 (95% CI 0.68­1.46, P=0.99) for the LL + VL genotypes. No particular allele variant was identified to exhibit an increased capacity to promote the development of highly aggressive prostate cancer (Gleason ≥7) or induce carcinogenesis at an earlier onset (<65 years of age). It was confirmed that in the population studied, the SRD5A2 V89L polymorphism was not associated with the risk of prostate cancer and SRD5A2 was not shown to be a key gene involved in prostate cancer development. Published data indicate that a combination of multiple genetic changes are required for prostate cancer development, rather than a single gene change. Therefore, it was hypothesized that high-throughput genotyping may be more effective than single nucleotide polymorphism detection.