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.

Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study

“…Although our sample size was quite large, our findings should be replicated by other studies before these methylation-based measures can be used for cancer risk prediction. In the case of lung cancer, our rate ratio estimate of 1.8 per SD for GrimAge is considerably larger than current estimates obtained for polygenic risk scores ( 32-35 ). For other cancers, our estimates are lower than for polygenic risk scores for colorectal, gastric, B-cell lymphoma, and prostate cancer and similar or greater for kidney and urothelial cancer ( 32-35 ).…”

“…In the case of lung cancer, our rate ratio estimate of 1.8 per SD for GrimAge is considerably larger than current estimates obtained for polygenic risk scores ( 32-35 ). For other cancers, our estimates are lower than for polygenic risk scores for colorectal, gastric, B-cell lymphoma, and prostate cancer and similar or greater for kidney and urothelial cancer ( 32-35 ). Combining polygenic and methylation aging scores may therefore be required to summarize risk associated with genetic factors and lifestyle or environmental exposures accumulated over the lifetime.…”

Evaluating polygenic risk scores in assessing risk of nine solid and hematologic cancers in European descendants

“…We estimated the proportion of the study participants who could be predicted, using PRS, at a given elevated risk (HR ≥2.0, 2.5 or 3.0), a risk level comparable to moderate-penetrance mutations (Table 4). We excluded five subjects from the previously published study 21 due to age <40 years.…”

“…2 This proportion of subjects who are predicted to have a 2-fold or higher risk of developing any cancer increases to 77.9% when we also consider the eight previously studied common cancers. 21 One notable exception is chronic lymphoid leukemia, for which risks are increased 4to 8-fold. 9,34 In this study, we also found that, unlike other cancers, the risk of chronic lymphoid leukemia was 4-fold higher in the top 5% group compared to the middle quintile group.…”

“…20 We recently evaluated the utility of PRS in identifying high-risk individuals at an elevated risk of eight common cancers that accounted for 59% of incident cases that were diagnosed in the United States in 2019. 21 Herein, we expanded our previous study to evaluate nine less common cancers that account for approximately 20.3% of new cancer cases and approximately 24.4% of cancer deaths in the world, according to the new global cancer data (GLOBOCAN 2018) estimates. 1 We estimated the percentage of individuals in the general population who can be predicted to have an at least twofold elevated risk of cancer, a risk level that is comparable to that conferred by moderate-penetrance mutations that have been included in clinical genetic testing for cancer risk assessment.…”