Development and Validation of a Genome-Wide Association Study Based Polygenic Risk Score for Prostate Cancer in an...

Area of Science:

• Genetics
• Oncology
• Bioinformatics

Background:

• Prostate cancer (PCa) is a significant health concern globally.
• Genetic factors play a crucial role in PCa development.
• Genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with PCa risk.

Purpose of the Study:

• To develop and validate a polygenic risk score (PRS) for estimating genetic susceptibility to prostate cancer (PCa).
• To assess the predictive performance of the PRS in a Taiwanese population.

Main Methods:

• A cohort of 1,015 PCa patients and 1,015 age-matched controls from the Taiwan Biobank (TWB) was used for PRS development.
• An independent validation cohort was assembled to confirm the PRS performance.
• Genotyping and imputation were performed to analyze approximately 690,000 SNPs and 15 million imputed SNPs.
• PRSice2 was utilized for PRS construction, with model performance evaluated using receiver operating characteristic (ROC) analysis and cross-validation (CV).

Main Results:

• A PRS was constructed using 24 significant SNPs, including those near KCNH7, HLA-DQA1, and PRNCR1.
• The PRS demonstrated strong predictive capability, achieving an area under the curve (AUC) of 0.824 (p=1.23×10⁻⁵⁰).
• Individuals in the highest PRS percentile showed a 34-fold increased risk of PCa compared to those in the lowest percentile (OR=34.37).
• The PRS model exhibited stable performance with mean accuracies of 0.75 (3-fold CV) and 0.76 (10-fold CV), and an AUC of 0.757 in the validation cohort.

Conclusions:

• The developed PRS is a robust predictor of PCa risk in the Taiwanese population.
• This PRS can potentially enhance risk stratification for PCa.
• The findings may guide the development of personalized interventions for prostate cancer.