SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease
PSA is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. PSA-based screening is widely debated due to false positives, overdiagnosis, and overtreatment.
The researchers in the present study hypothesized that Polygenic Risk Scores (PRS) based on aggregation of common genetic variants offer a promising way to stratify individual risk, independent of PSA or family history. Following completion of a pilot study, the BARCODE1 study was designed to prospectively test whether using a Polygenic Risk Score (PRS) could improve targeted screening effectiveness.
STUDY DESIGN:
BARCODE1 is a prospective, population-based, genetic risk-stratified screening study which included 6,393 men aged 55-69 yrs, with their Polygenic Risk Score calculated and recruited from 130 UK general practices. Germline DNA from saliva was used to calculate Polygenic Risk Score based on 130 known prostate cancer SNPs (Single Nucleotide Polymorphisms). Single Nucleotide Polymorphisms (SNPs “snips”) are variations in certain genes of a person’s DNA that can increase or decrease an individual’s risk of susceptibility to the disease. Men in the top 10% of the Polygenic Risk Score distribution (N=745) were invited for further screening with multiparametric MRI (mpMRI) and transperineal biopsy, regardless of PSA level.
KEY RESULTS:
MRI/biopsy was performed in 468 of these 745 men and 40% (N=187) were diagnosed with prostate cancer. Of the 187 participants, 103 men (55.1%) had clinically significant (Grade Group ≥2) cancer.
High-risk (Grade Group 3-5) cancer was found in 21.4% (N=40) of diagnosed men. These cancers typically qualify for radical therapy.
Current UK PSA thresholds (PSA >3.0 ng/mL) would have missed 71.8% of clinically significant cancers found through Polygenic Risk Score-based screening. Notably, 52% of all clinically significant cases had PSA <3.0 ng/mL, reinforcing the inadequacy of PSA-alone screening.
Estimated overdiagnosis (Grade Group 1 tumors) was 15.6–20.8%, comparable to, or lower than rates seen in PSA-based screening.
mpMRI-negative but Polygenic Risk Score-positive men still had a 6.4% clinically significant prostate cancer detection rate, underscoring Polygenic Risk Score value beyond imaging.
CONCLUSION:
Polygenic Risk Score-based screening detected more clinically significant prostate cancers than PSA or mpMRI alone. Combining Polygenic Risk Score with age and family history may help optimize risk-based screening strategies. One important limitation of this study is that participants were mostly educated men of European ancestry. These results may therefore not generalize to other ethnic groups or broader populations. Further research is needed to assess cost-effectiveness, utility across ancestries, and integration of genomics into national screening programs.
Polygenic Risk Score for Prostate Cancer Screening. McHugh JK, Bancroft EK, Saunders E, et al. for the BARCODE1 Steering Committee and Collaborators. N Engl J Med 2025;392:1406-1417
