Abstract 2319: Pan-cancer analysis of polygenic risk scores reveals improvement in risk prediction and stratification

Genome-wide association studies (GWAS) have identified a wealth of germline risk variants, but the clinical impact of these findings has been modest. In response, GWAS results have been used to create polygenic risk scores (PRS) that summarize an individual9s genetic susceptibility profile. We assembled PRS for 16 cancers in the UK Biobank (n=413753, 52 to 4170 incident cases) to quantify the extent to which common, low-penetrance risk variants improve upon risk discrimination provided by family history and modifiable exposures. PRS were derived by abstracting variants with minor allele frequency ≥0.01 and P An interesting initial observation was that replacing self-reported family history of cancer with the PRS improved prediction accuracy for prostate (C=0.763, ΔC=0.047), breast (C=0.618, ΔC=0.060), and colorectal (C=0.708, ΔC=0.029) cancers. Incorporating the PRS in addition to all risk factors available in our data resulted in substantial gains in risk discrimination for several cancer sites: testes (CPRS=0.766, ΔC=0.138), thyroid (CPRS=0.692, ΔC=0.099), leukemia (CPRS=0.756, ΔC=0.061), breast (CPRS=0.631, ΔC=0.060), prostate (CPRS=0.768, ΔC=0.051), melanoma (CPRS=0.664, ΔC=0.042), and colon/rectum (CPRS=0.716, ΔC=0.030). Next, we assessed risk stratification by examining 5-year absolute risk trajectories. Stratifying by percentiles of PRS (high: ≥80%, average: >20% to Lastly, we quantified the proportion of cancer risk at the population level that is attributed to genetic vs. modifiable risk factors. High genetic risk (PRS≥80th percentile) explained between 4.0% (lung) and 30.3% (testicular) of new cases. For many cancers the attributable fraction (AF) for PRS exceeded the AF for modifiable risk factors or family history: thyroid (AFPRS=0.268, P=1.7 × 10−9), prostate (AFPRS=0.232, P=5.5 × 10−158), colorectal (AFPRS=0.167, P=9.2 × 10−50), breast (AFPRS=0.166, P=2.6 × 10−85), and melanoma (AFPRS=0.139, P=1.3 × 10−23). PRS was the only significant contributor to cancer risk, other than age and sex, for testicular cancer (AFPRS=0.303, P=4.5 × 10−4), leukemia (AFPRS=0.269, P=4.5 × 10−4), and lung cancer in never smokers (AFPRS=0.077, P=0.045). In summary, we provide evidence from an independent validation cohort that supports the potential clinical utility of PRS in complementing conventional cancer risk factors to improve and refine risk prediction. Citation Format: Linda Kachuri, Rebecca E. Graff, Karl Smith-Byrne, Travis J. Meyers, Sara R. Rashkin, Elad Ziv, John S. Witte, Mattias Johansson. Pan-cancer analysis of polygenic risk scores reveals improvement in risk prediction and stratification [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2319.