Germline polygenic score for prostate cancer aggressiveness

Area of Science:

• Genetics
• Oncology
• Urology

Background:

• Prostate cancer (PCa) risk stratification often relies on clinicopathologic features.
• Genetic factors can influence PCa progression and aggressiveness.
• A novel germline polygenic risk score (PRSagg) was developed to predict aggressive PCa.

Purpose of the Study:

• To develop and validate a germline polygenic risk score (PRSagg) for predicting prostate cancer aggressiveness.
• To assess the association of PRSagg with PCa grade group at diagnosis and unfavorable outcomes during active monitoring.

Main Methods:

• Developed PRSagg using genome-wide association study in 38,688 PCa patients from the Million Veteran Program (MVP).
• Tested PRSagg associations with grade group and unfavorable outcomes in MVP and validated in PRACTICAL Consortium and ProtecT trial cohorts.
• Adjusted for age, genetic ancestry, PCa risk score (PHS601), and PSA risk score (PRSPSA).

Main Results:

• PRSagg (172 variants) was associated with higher grade group at diagnosis (OR=1.53) and increased risk of unfavorable outcomes (OR=1.13) in MVP.
• Findings were confirmed in external datasets; PRSagg associated with higher grade group (OR=1.09) and metastasis risk (OR=2.15) in ProtecT.
• High PRSagg combined with low genetic risk of PSA elevation indicated highest aggressive disease risk in MVP participants.

Conclusions:

• Germline variants, quantified by PRSagg, are independently associated with prostate cancer aggressiveness.
• PRSagg may enhance risk stratification for active surveillance in men diagnosed with PCa.
• Further research into germline influence on tumor evolution and personalized surveillance is warranted.