Prostate cancer (PCa) remains one of the most critical global health challenges in men, ranking as the most frequently diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death worldwide [1]. In Hungary, PCa is the leading male malignancy, with 6,660 new cases and 1,554 deaths recorded in 2022, making it the third leading cause of cancer-specific mortality among Hungarian men [2, 3]. Established risk factors include older age, positive family history, and African ancestry [4]. Approximately 20% of patients develop high-risk tumors that may progress to metastatic disease, and PCa-related mortality remains substantial despite advances in diagnosis and treatment [5, 6].

Recent advances have highlighted the role of genetic factors in PCa susceptibility and prognosis. Although hereditary predisposition is well established, interactions between genetic and biological factors contribute to individual disease risk [7, 8]. Single nucleotide polymorphisms (SNPs) are common genetic variants [9], and genome-wide association studies (GWAS) have identified approximately 70–100 PCa-associated SNPs, supporting a polygenic model in which multiple common variants contribute to inherited disease susceptibility [8].

Among candidate susceptibility genes, RNASEL, ELAC2, and MSR1 have been implicated in PCa risk and aggressiveness [8, 10–12]. However, associations between individual variants and PCa risk remain inconsistent across populations, potentially reflecting differences in genetic background and biological pathways including immune response, apoptosis, DNA damage response, and inflammation [8]. The RNASEL rs486907 variant has been associated with altered enzymatic activity, apoptosis, PCa susceptibility, and disease aggressiveness, although conflicting findings have also been reported [13, 14]. Similarly, ELAC2 variants rs5030739 and rs17552022 and MSR1 variants rs918 and rs1904577 have shown associations with PCa susceptibility or aggressive characteristics in some cohorts, but these findings have not been consistently replicated [10, 14].

In addition, KLK3 rs17632542 has been associated with PCa aggressiveness, biopsy positivity, and higher-risk disease [15].

Although most PCa GWAS have been conducted in PSA-screened Western populations, Central and Eastern European cohorts remain underrepresented [16]. Therefore, the aim of the present study was to investigate the association between selected polymorphisms in RNASEL, ELAC2, MSR1, and KLK3 genes and prostate cancer susceptibility in a Hungarian population, as well as their potential associations with clinicopathological parameters.

This case-control study included 103 histologically confirmed prostate cancer patients and 103 healthy controls. The mean age of the patients was 68.9 ± 6.2 years, while the mean age of healthy controls was 67.2 ± 5.8 years. Based on serum PSA levels, 50 patients (48.5%) had PSA values ≤ 10 ng/mL, 21 patients (20.4%) had PSA levels between 10 and 20 ng/mL, while 32 patients (31.1%) presented with PSA levels >20 ng/mL. A Gleason score <7 was observed in 22 patients (21.4%), whereas 81 patients (78.6%) had a Gleason score ≥7. According to the EAU guideline–based clinical risk stratification using both PSA level and Gleason score, 50 patients (48.5%) were classified as low-risk, 21 patients (20.4%) as intermediate-risk, and 32 patients (31.1%) as high-risk disease (Table 3). During the genetic analysis, genotype and allele frequencies of six selected polymorphisms in the MSR1, ELAC2, KLK3 and RNASEL genes were determined in both studied groups. These distribution data, along with the corresponding odds ratios (OR), 95% confidence intervals (CI), and p-values, are summarized in Table 2. All investigated polymorphisms were in Hardy–Weinberg equilibrium in the control group. Among the evaluated loci, RNASEL c.1385G>A; p.Arg462Gln (rs486907) was the only variant to show a statistically significant association with prostate cancer risk. The GG homozygous normal genotype was more frequent among prostate cancer patients (51.5%) compared to controls (35.9%), whereas the heterozygous GA genotype occurred more frequently in the control group (46.6% vs. 26.2%). The A allele frequency was 35.4% in patients and 40.8% in controls. Due to the exploratory nature of these 103 cases versus 103 control study, the reported associations are nominally significant, as multiple testing corrections were omitted. Descriptive comparison with external reference datasets was performed to position the current cohort within a wider population context (Table 4). The RNASEL rs486907 A-allele frequency among Hungarian controls (0.408) was broadly consistent with the European reference values from the 1000 Genomes Project (0.371). In our prostate cancer cohort, the A-allele frequency stood at 0.354. For comparison, the global meta-analysis by Zuo et al. yielded frequencies of 0.303 for affected individuals and 0.290 for healthy controls. Association analysis demonstrated a statistically significant protective effect of the variant under the dominant model in the investigated population (OR = 0.53; 95% CI: 0.30–0.92; p = 0.025). Furthermore, in age-adjusted logistic regression analysis, this protective association of the RNASEL rs486907 dominant model remained statistically significant (OR = 0.56, p = 0.046), suggesting that the observed association was independent of age. The distribution of RNASEL rs486907 genotypes in prostate cancer patients and controls is illustrated in Figure 1. No statistically significant associations with prostate cancer susceptibility were observed for the genetic variants within the MSR1, ELAC2, and KLK3 genes.

The present study investigated the association between selected polymorphisms in RNASEL, ELAC2, MSR1, and KLK3 genes and prostate cancer susceptibility in a Hungarian population. Among the investigated variants, only the RNASEL rs486907 polymorphism demonstrated a statistically nominally significant association with prostate cancer risk, suggesting a potential protective effect in the studied cohort.

RNASEL is considered a biologically plausible candidate gene in prostate cancer susceptibility due to its role in interferon-mediated antiviral defense, apoptosis, and inflammatory signaling pathways [11]. The rs486907 (p.Arg462Gln) polymorphism has previously been associated with altered RNASEL enzymatic activity and impaired apoptotic function [19]. Several studies reported associations between this variant and increased prostate cancer susceptibility or more aggressive disease phenotypes, including higher Gleason score and familial prostate cancer [10, 14]. However, the available literature remains inconsistent, as other investigations described either no association or even protective effects of specific RNASEL variants [13, 20]. These contradictory findings suggest substantial population-dependent variability and support the hypothesis that inherited susceptibility to prostate cancer may differ between ethnic and geographic populations. To place these findings in a broader population context, the RNASEL rs486907 A-allele frequencies observed in the present cohort were compared descriptively with data from the 1000 Genomes Project and the meta-analysis by Zuo et al. (Table 4). The A-allele frequency in the Hungarian control group (0.408) was broadly comparable to that reported for the European reference population (0.371). The corresponding frequency among prostate cancer patients was 0.354. In the pooled meta-analysis by Zuo et al., the A-allele frequencies were 0.303 among prostate cancer cases and 0.290 among controls [10, 17, 18]. This discrepancy suggests that the association between RNASEL rs486907 and prostate cancer risk may vary across populations and study cohorts. As no formal statistical comparison with external reference populations was performed, these differences should be interpreted descriptively.

Mechanistically, the RNASEL rs486907 (p.Arg462Gln) variant alters protein function and leads to a threefold reduction in enzymatic activity [19, 21]. While compromised RNASEL activity is traditionally linked to impaired apoptosis and viral clearance [21, 22], it is hypothesized that a dampened immune response may conversely mitigate chronic intraprostatic inflammation.

Given that chronic inflammation is an important contributor to prostate carcinogenesis [23, 24], the reduced enzymatic activity of the Gln462 variant might theoretically exert a protective effect in specific genetic backgrounds by suppressing tumor-promoting inflammatory microenvironments. However, this proposed protective mechanism remains purely hypothetical and speculative, as it has not been directly demonstrated or functionally validated for the rs486907 variant.

The protective association observed in the present study is consistent with previous reports suggesting that certain RNASEL variants or haplotypes may reduce prostate cancer risk in specific populations [13, 20]. Differences in allele frequencies, linkage disequilibrium patterns, environmental exposures, and gene–gene interactions may contribute to these heterogeneous findings. Furthermore, prostate cancer is considered a polygenic and multifactorial disease in which the individual effect of a single polymorphism is likely modest and influenced by additional genetic and non-genetic factors [25].

No statistically significant associations were observed for the investigated ELAC2, MSR1, or KLK3 polymorphisms. Although previous studies reported potential associations between these variants and prostate cancer susceptibility or aggressiveness, the findings have not been consistently reproducible across different cohorts [10, 14]. The lack of significant associations in the present study may partially be explained by population-specific genetic differences and the relatively limited sample size. Notably, our PCa cohort was characterized by a high proportion of aggressive disease, with 78.6% of patients presenting with a Gleason score ≥7 and 31.1% demonstrating high-risk clinical features according to EAU stratification [26]. The lack of statistically significant associations for the ELAC2 [27], MSR1 [14], and KLK3 [28] variants within our study could potentially be attributed to this clinical skewness, as these markers might exert different risk profiles in low-grade or indolent prostate tumors, which were underrepresented in our sample.

The present study has several limitations. First, the sample size was relatively limited, which may reduce statistical power, complicate the identification of variants with small effect sizes, and increase the risk of false-negative findings. Accordingly, further stratification into clinical subgroups, such as by Gleason score or PSA categories, was not performed, as sub-analyzing smaller groups would have further reduced statistical power and increased the risk of spurious associations. Second, this was a single-center study involving a Hungarian population; therefore, the results may not be generalizable to other ethnic groups. Third, correction for multiple testing was not applied due to the exploratory nature of the study and the limited cohort size. Consequently, the observed borderline significant associations must be interpreted with caution and require independent validation in larger, well-powered cohorts. In addition, detailed clinical data were not available for the control group, limiting further comparative analyses.

Despite these limitations, the study also has important strengths. All prostate cancer cases were histologically confirmed, the investigated cohort was clinically well characterized, and genotyping was performed using PCR-based Sanger sequencing, providing reliable genetic analysis. Furthermore, data regarding prostate cancer susceptibility polymorphisms in Central and Eastern European populations remain limited, highlighting the potential relevance of the present findings.

Importantly, the protective association of the RNASEL rs486907 variant remained statistically significant even after adjusting for age in the multivariate logistic regression analysis (OR = 0.56, 95% CI: 0.32–0.99, p = 0.046). Since advanced age is the strongest non-modifiable risk factor for PCa [29], this age-independent persistence is noteworthy. However, given the limited sample size and the fact that this finding is based on nominal significance, it should be treated as exploratory rather than a definitive genetic predisposition. Moreover, because its individual effect size is too small for direct, standalone clinical risk prediction or immediate therapeutic application, we instead highlight its value as a potential candidate for future, larger-scale Central European polygenic risk models. Furthermore, the adherence of all investigated loci to the Hardy–Weinberg equilibrium in the control group supports the quality of genotyping and indicates no apparent deviation that would raise concerns regarding genotyping errors or major population stratification [30].