A genetic risk score to personalize prostate cancer screening, applied to population data.
Huynh-Le M-P., Fan CC., Karunamuni R., Walsh EI., Turner EL., Lane JA., Martin RM., Neal DE., Donovan JL., Hamdy FC., Parsons JKK., Eeles RA., Easton DF., Kote-Jarai Z., Amin Al Olama A., Benlloch Garcia S., Muir K., Grönberg H., Wiklund F., Aly M., Schleutker J., Sipeky C., Tammela T., Nordestgaard BG., Key TJ., Travis RC., Pharoah PDP., Pashayan N., Khaw K-T., Thibodeau SN., McDonnell SK., Schaid DJ., Maier C., Vogel W., Luedeke M., Herkommer K., Kibel AS., Cybulski C., Wokolorczyk D., Kluzniak W., Cannon-Albright LA., Brenner H., Schöttker B., Holleczek B., Park JY., Sellers TA., Lin H-Y., Slavov CK., Kaneva RP., Mitev VI., Batra J., Clements JA., Spurdle AB., Teixeira MR., Paulo P., Maia S., Pandha H., Michael A., Mills IG., Andreassen OA., Dale AM., Seibert TM.
BACKGROUND: A polygenic hazard score (PHS)-the weighted sum of 54 SNP genotypes-was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. METHODS: UK population incidence data (Cancer Research UK) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using hazard ratios estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age-when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-years-standard risk)-was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. RESULTS: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-years-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. CONCLUSIONS: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. IMPACT: Personalized genetic risk assessments could inform prostate cancer screening decisions.