Multi-cancer risk models combining non-genetic factors and polygenic risk scores achieved 10-year risk AUCs of 0.60 in females and 0.61 in males, identifying ~24% of US adults as high risk.
Does a multi-cancer risk prediction model incorporating polygenic risk scores and non-genetic factors accurately stratify cancer risk in a non-Hispanic White population?
A multi-cancer risk prediction model combining non-genetic factors and polygenic risk scores provides meaningful risk stratification, identifying nearly a quarter of US adults as having moderate to high 10-year cancer risk.
Absolute Event Rate: 0% vs 0%
Abstract Background: Multiple risk factors are shared across different cancers, yet risk assessment and prevention strategies remain largely site-specific. Meanwhile, multi-cancer detection tests are emerging as complementary approaches to site-specific screening strategies such as mammography, colonoscopy, and low-dose CT lung scans. Multi-cancer risk prediction could provide a more holistic understanding of an individual’s cancer risk, with the potential to improve risk-stratified prevention and screening strategies across multiple cancer types. Methods: We developed absolute risk models for 14 cancer sites using published non-genetic risk models incorporating 26 risk factors, together with established polygenic risk score (PRS) for each cancer site, using the Individualized Coherent Absolute Risk Estimator (iCARE) tool to integrate relative risk parameters, risk-factor distributions, population incidence rates, and mortality rates. We extended iCARE to estimate risk across multiple cancer sites over specified time intervals. Calibration (expected/observed (E/O) risk) and discrimination (area under the curve (AUC)) of site-specific and combined multi-cancer risk predictions were prospectively evaluated in the non-Hispanic White population in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Multi-cancer risk stratification for the US non-Hispanic White population was projected by applying our model with age specific incidence and mortality rates to a reference population derived from the National Health and Nutrition Examination Survey, the National Health Interview Survey, and the Breast Cancer Surveillance Consortium. Results: Validation in PLCO showed comparable risk stratification between the sexes but better calibration for females (multi-cancer 10-yr risk E/O = 1.05 (95% CI: 1.03-1.07), AUC = 0.60) than males (E/O = 0.76 (95% CI: 0.75-0.77), AUC = 0.61). Between the first and last decile of predicted 10-year risk, the corresponding observed risk ranges 3-20% in females and 7-30% in males. Multi-cancer risk projections for the non-Hispanic White US reference population showed that 24% of males and 23% of females aged 18-74 are at moderate to high risk (10-year absolute risk ≥10%). Conclusion: Multi-cancer risk prediction models combining non-genetic risk factors and PRS demonstrate meaningful risk stratification. Future studies will include calibration, validation, and projection of these models in US non-White populations. Such models may support counseling on lifestyle interventions that influence multiple cancer risks and help identify high-risk individuals for emerging multi-cancer screening approaches such as liquid biopsy tests. However, further model development and evaluation is needed to ensure optimal performance across population groups. Citation Format: Emily L. Norton, Thomas Ahearn, Srijon Mukhopadhyay, Jeya Balasubramanian, Elle Kim, Sara Li, Parichoy Pal Choudhury, Montserrat García-Closas, Nilanjan Chatterjee. Validation and population projection of multi-cancer risk incorporating polygenic risk scores and non-genetic factors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3586.
Norton et al. (Fri,) reported a other. Multi-cancer risk models combining non-genetic factors and polygenic risk scores achieved 10-year risk AUCs of 0.60 in females and 0.61 in males, identifying ~24% of US adults as high risk.