Common genetic variants in prostate cancer risk prediction--results from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3)

Abstract

Background: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age.

Methods: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data.

Results: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile).

Conclusions: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening.

Impact: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited.

Figure 1

Association between decile categories for number of risk alleles carried and prostate cancer risk stratified by disease aggressiveness and age of onset. Decile-specific odds ratios were estimated based on the imputed dataset (10,459 cases and 10,790 controls). All analyses were adjusted for age and cohort. a) Localized cases (5,721 cases) b) Aggressive cases (2,641 cases) c) ≤65 years (3,315 cases and 4,214 controls) d) >65 years (7,144 cases and 6,576 controls).

Figure 2

Receiver Operating Characteristic (ROC) curve for genetics only and genetics plus family history.

Figure 3

Estimated distribution of ten-year absolute risks of prostate cancer among 50-year–old U.S white men as a function of genetic risk.