The study, published in Pathology and Oncology Research, arrives at a moment when prostate cancer is a mounting burden in Hungary. It is the leading male malignancy in the country, with 6,660 new cases and 1,554 deaths recorded in 2022, ranking third among cancer-specific causes of death for Hungarian men. Globally, prostate cancer is the most frequently diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death in men. Established risk factors include older age, positive family history, and African ancestry, and approximately 20 percent of patients develop high-risk tumors that may progress to metastatic disease. Against that backdrop, identifying inherited genetic factors that modulate risk has become a major goal of cancer genetics, and the Hungarian team set out to fill a conspicuous gap: while most prostate cancer genome-wide association studies have been conducted in PSA-screened Western populations, Central and Eastern European cohorts remain strikingly underrepresented.

The researchers focused on four genes that have long fascinated prostate cancer geneticists because of their biology. RNASEL encodes ribonuclease L, a key executioner of the interferon-mediated antiviral defense pathway that also participates in apoptosis and inflammatory signaling. ELAC2, historically known as HPC2, was one of the first prostate cancer susceptibility loci identified through linkage analysis. MSR1 encodes the macrophage scavenger receptor 1, a protein involved in the innate immune response, and KLK3 encodes prostate-specific antigen, the familiar PSA protein used in clinical screening. Genome-wide association studies have collectively identified roughly 70 to 100 prostate cancer-associated single nucleotide polymorphisms, supporting a polygenic model in which many common variants, each with a modest individual effect, jointly shape inherited disease susceptibility.

The methodology was deliberately rigorous for a modest-sized cohort. The 103 patients were men who underwent prostate biopsy at the Department of Urology in Pécs and received a histopathological diagnosis of prostate cancer, while the 103 controls were asymptomatic men drawn from the biobank of the Department of Medical Genetics, all with normal age-specific serum PSA levels below 4.0 nanograms per milliliter and negative digital rectal examinations, a screening strategy designed to minimize the chance of including occult or latent cancers in the comparison group. Genomic DNA was isolated from peripheral blood and the selected variants were genotyped using PCR amplification followed by Sanger direct sequencing on an Applied Biosystems 3500 Genetic Analyzer. The sequencing call rate reached 100 percent, missing genotype frequencies stayed below 1 percent, and random re-sequencing of 10 percent of the samples confirmed 100 percent concordance, underscoring the reliability of the genetic calls.

The clinical picture of the patient group was notably aggressive. The mean patient age was 68.9 years, and 78.6 percent of patients presented with a Gleason score of 7 or higher, while 31.1 percent fell into the high-risk category under European Association of Urology stratification based on PSA level and Gleason score. Only 48.5 percent were classified as low-risk disease. All investigated polymorphisms were in Hardy-Weinberg equilibrium in the control group, a quality check that argues against genotyping errors or major population stratification. Yet when the genotype distributions were compared, only one locus separated the two groups: the RNASEL c.1385G>A variant, which changes the amino acid arginine at position 462 to glutamine, p.Arg462Gln.

The pattern in the raw numbers was clear. The GG homozygous reference genotype was found in 51.5 percent of prostate cancer patients but only 35.9 percent of controls, whereas the heterozygous GA genotype was substantially more frequent in the healthy group, appearing in 46.6 percent of controls versus 26.2 percent of patients. The A allele frequency was 35.4 percent in patients and 40.8 percent in controls. Analyzed under a dominant model, in which heterozygous and variant homozygous genotypes are pooled against the reference homozygote, the variant conferred a nominally significant protective effect. None of the variants in KLK3, MSR1, or ELAC2, including the MSR1 c.*516G>A and c.1223-3957C>T variants, the ELAC2 p.Thr631 and p.Ala541Thr variants, and the KLK3 p.Ile179Thr variant, showed a statistically significant association with disease susceptibility.

What makes the RNASEL result biologically provocative is the direction of the effect. Functional studies have shown that the Gln462 variant reduces the enzymatic activity of ribonuclease L by roughly threefold, and compromised RNASEL activity has traditionally been linked to impaired apoptosis and deficient viral clearance, which sounds like a recipe for higher cancer risk, not lower. Several earlier studies indeed associated the variant with increased susceptibility or more aggressive disease, including higher Gleason scores and familial prostate cancer. But the Pécs team offers a speculative counter-hypothesis: chronic inflammation is an important contributor to prostate carcinogenesis, so a dampened antiviral and inflammatory response might, paradoxically, mitigate the chronic intraprostatic inflammation that fuels tumor development. The authors are careful to stress that this protective mechanism remains hypothetical and has not been directly demonstrated or functionally validated for rs486907.

The population context adds another layer of intrigue. The A-allele frequency of 0.408 in the Hungarian control group aligns broadly with the European reference value of 0.371 from the 1000 Genomes Project, but it stands well above the frequencies reported for East Asian (0.242), American (0.223), and African (0.067) populations. Meanwhile, a pooled meta-analysis by Zuo and colleagues found A-allele frequencies of 0.303 among prostate cancer cases and 0.290 among controls, a much narrower gap than the one observed in Hungary. These discrepancies, which the authors note are descriptive rather than formally tested, suggest that the relationship between this variant and prostate cancer risk may genuinely vary across ethnic and geographic populations, shaped by differences in allele frequencies, linkage disequilibrium patterns, environmental exposures, and gene-gene interactions.

The researchers are candid about the limitations of their work. The sample size of 103 cases and 103 controls is relatively small, which limits statistical power, complicates the detection of variants with small effect sizes, and increases the risk of false-negative findings for the genes that showed no association. No correction for multiple testing was applied, given the exploratory nature of the study, so the significance of the RNASEL finding is nominal and must be treated as exploratory rather than definitive. Detailed clinical data were unavailable for the control group, and the clinical skewness of the patient cohort toward aggressive disease might partly explain why markers like ELAC2, MSR1, and KLK3, which may exert different risk profiles in low-grade or indolent tumors, failed to show signals here. Subgroup analyses by Gleason score or PSA category were deliberately avoided because splitting small groups further would have invited spurious associations.

Even with those caveats, the study’s strengths and implications are considerable. All cancer cases were histologically confirmed, the cohort was clinically well characterized, and PCR-based Sanger sequencing provided highly reliable genotyping. The authors emphasize that the effect size of a single polymorphism is far too small for standalone clinical risk prediction or immediate therapeutic application, but they position RNASEL rs486907 as a candidate for future, larger-scale Central European polygenic risk scores, the kind of multi-variant models that could eventually sharpen prostate cancer screening decisions. Data on prostate cancer susceptibility polymorphisms in Central and Eastern European populations remain scarce, making this Hungarian contribution a meaningful data point in a neglected region. As the authors conclude, further investigations involving larger cohorts are warranted to validate the observation, but the message is already compelling: the genetic architecture of prostate cancer risk is population-specific, and a gene variant that protects one population may tell a very different story in another.

Subject of Research: Association of RNASEL, ELAC2, MSR1 and KLK3 gene polymorphisms with prostate cancer susceptibility in a Hungarian case-control cohort

Article Title: Association of selected ELAC2, MSR1, RNASEL and KLK3 polymorphisms with prostate cancer susceptibility in a Hungarian cohort

Article References: Kovacs, S., Szalai, R., Barati, L., & Hadzsiev, K. (2026). Association of selected ELAC2, MSR1, RNASEL and KLK3 polymorphisms with prostate cancer susceptibility in a Hungarian cohort. Pathology & Oncology Research, 32, Article 1612550. https://doi.org/10.3389/pore.2026.1612550

Image Credits: AI Generated

DOI: 10.3389/pore.2026.1612550

Keywords: prostate cancer, RNASEL, rs486907, ELAC2, MSR1, KLK3, single nucleotide polymorphism, genetic susceptibility, Hungarian cohort, case-control study, inflammation, polygenic risk