MicroRNA Biogenesis Pathway Gene Variants Are Associated with Prostate Cancer Susceptibility

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Prostate cancer (PrC) is a prevalent male malignancy globally.
• Genetic factors influencing PrC risk are not fully understood, particularly in diverse ethnic groups.
• The role of genetic variations in microRNA (miRNA) biogenesis pathways in PrC susceptibility requires further investigation.

Purpose of the Study:

• To investigate the association between genetic variations in miRNA biogenesis pathway genes and PrC risk.
• To evaluate the utility of polygenic risk scores (PRSs) for predicting PrC susceptibility.
• To assess the combined predictive value of PRS and prostate-specific antigen (PSA) for PrC.

Main Methods:

• A case-control study was conducted with 532 PrC patients and 550 controls from the Volga-Ural region.
• Twenty-one single nucleotide polymorphisms (SNPs) in miRNA biogenesis genes were analyzed using single-variant and polygenic approaches.
• Weighted and unweighted polygenic risk scores (PRSs) were constructed and evaluated for association with PrC risk and discriminatory performance.

Main Results:

• The SNP rs595055 in the AGO1 gene was significantly associated with PrC risk after multiple testing correction.
• The weighted PRS demonstrated a strong association with PrC risk (OR per SD increase = 1.63, P = 1.37 × 10^-13) and moderate discriminatory performance (AUC = 63.1%).
• Individuals in the highest PRS quartile had threefold higher odds of PrC compared to the lowest quartile. Combining PRS with PSA improved discrimination (AUC = 68.1%).

Conclusions:

• Genetic variations within miRNA biogenesis pathway genes contribute to prostate cancer susceptibility.
• Pathway-based polygenic risk stratification shows promise for identifying individuals at higher risk, particularly in understudied populations.
• The developed PRS, especially when combined with PSA, can enhance PrC risk prediction.