Evaluating the Utility of Polygenic Risk Scores in Identifying High-Risk Individuals for Eight Common Cancers

Abstract

Background: Genome-wide association studies have identified common genetic risk variants in many loci associated with multiple cancers. We sought to systematically evaluate the utility of these risk variants in identifying high-risk individuals for eight common cancers.

Methods: We constructed polygenic risk scores (PRS) using genome-wide association studies-identified risk variants for each cancer. Using data from 400 812 participants of European descent in a population-based cohort study, UK Biobank, we estimated hazard ratios associated with PRS using Cox proportional hazard models and evaluated the performance of the PRS in cancer risk prediction and their ability to identify individuals at more than a twofold elevated risk, a risk level comparable to a moderate-penetrance mutation in known cancer predisposition genes.

Results: During a median follow-up of 5.8 years, 14 584 incident case patients of cancers were identified (ranging from 358 epithelial ovarian cancer case patients to 4430 prostate cancer case patients). Compared with those at an average risk, individuals among the highest 5% of the PRS had a two- to threefold elevated risk for cancer of the prostate, breast, pancreas, colorectal, or ovary, and an approximately 1.5-fold elevated risk of cancer of the lung, bladder, or kidney. The areas under the curve ranged from 0.567 to 0.662. Using PRS, 40.4% of the study participants can be classified as having more than a twofold elevated risk for at least one site-specific cancer.

Conclusions: A large proportion of the general population can be identified at an elevated cancer risk by PRS, supporting the potential clinical utility of PRS for personalized cancer risk prediction.

Figure 1.

Distribution of standardized PRS between case patients and noncase patients. Distribution of standardized PRS was displayed for cancer of the (A) prostate, (B) breast, (C) colorectal, (D) and lung. Case patients (solid line) have a higher PRS value compared with noncase patients (dashed line) for all four cancers. PRS was standardized by subtracting the mean and dividing by the standard deviation. PRS = polygenic risk score.

Figure 2.

Cumulative risk of cancer over follow-up period by percentile of PRS. Study participants were divided into 50 groups according to the percentile of PRS (each 2%). Cumulative risk over a 5.8-year follow-up period of the UK Biobank cohort was displayed for cancers of the (A) prostate, (B) breast, (C) colorectal, (D) and lung. PRS = polygenic risk score.

Figure 3.

Five-year absolute risks of site-specific cancers by PRS groups. Five-year absolute risk of developing cancer of (A) prostate, (B) breast, (C) colorectal, (D) and lung. The horizontal lines show the estimated 5-year risk for individuals with median PRS (45%-55%) at the age of 50 years for (B) breast cancer or (C) colorectal cancer. PRS = polygenic risk score.