Development and validation of a simple prostate cancer risk prediction model based on age, family history, and polygenic risk

Abstract

Background: Accurate prostate cancer risk assessment will enable identification of men who are at increased risk of the disease. Using the UK Biobank population-based cohort, we developed and validated a simple model comprising age, family history, and a polygenic risk score (PRS) to predict 5-year risk of prostate cancer.

Methods: Eligible participants were unaffected Caucasian men aged 40-69 years at their baseline assessment who had genotyping data available and had completed 6 or more weeks of follow-up. Family history was the number of affected first-degree relatives: 0, 1, or 2+. We used 264 single-nucleotide polymorphisms (SNPs) of a previously developed 269-SNP PRS and population standardized the PRS to have a mean of 1. Age was categorized into 10-year groups: 40-49, 50-59, and 60-69. In a 70% training data set, we used Cox regression with age as the time axis to model family history, PRS, and age group. The model estimates were used with prostate cancer incidences to derive 5-year risks of prostate cancer. Using 5 years of follow-up in a 30% testing data set, the model was tested in terms of its association per quintile of risk, discrimination, and calibration.

Results: Of the 198 334 eligible participants, 8996 (4.5%) were diagnosed with incident prostate cancer during follow-up and had a mean age of 67.9 (SD = 5.8) years at diagnosis. The best-fitting model included the PRS, family history, 10-year age group, interactions between age and PRS, and age and family history. In the 30% testing data set with follow-up limited to 5 years, the hazard ratio per SD of 5-year risk was 3.058 (95% confidence interval [CI], 2.720-3.438) and the Harrell's C-index was 0.811 (95% CI, 0.800-0.821). Overall, there were 1088 observed and 1159.1 expected prostate cancers, a standardized incidence ratio of 0.939 (95% CI, 0.885-0.996).

Conclusions: Men at increased risk of prostate cancer could benefit from informed discussions around the risks and benefits of available options for screening for prostate cancer. Although the model was developed in Caucasian men, it can be used with ethnicity-specific polygenic risk and incidence rates for other populations.

Keywords: absolute risk; cohort study; polygenic risk score.