Risk Stratification for Early-Onset Colorectal Cancer Using a Combination of Genetic and Environmental Risk Scores: An International Multi-Center Study

Alexi N. Archambault, Jihyoun Jeon, Yi Lin, Minta Thomas, Tabitha A. Harrison, D. Timothy Bishop, Hermann Brenner, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Jane C. Figueiredo, Steven Gallinger, Stephen B. Gruber, Marc J. Gunter, Feng Guo, Michael Hoffmeister, Mark A. Jenkins, Temitope O. Keku, Loïc Le Marchand, Li LiVictor Moreno, Polly A. Newcomb, Rish Pai, Patrick S. Parfrey, Gad Rennert, Lori C. Sakoda, Jeffrey K. Lee, Martha L. Slattery, Mingyang Song, Aung Ko Win, Michael O. Woods, Neil Murphy, Peter T. Campbell, Yu Ru Su, Iris Lansdorp-Vogelaar, Elisabeth F.P. Peterse, Yin Cao, Anne Zeleniuch-Jacquotte, Peter S. Liang, Mengmeng Du, Douglas A. Corley, Li Hsu, Ulrike Peters, Richard B. Hayes*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Scopus)


Background: The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants. Methods: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve. Results: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores. Conclusions: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.

Original languageEnglish
Pages (from-to)528-539
Number of pages12
JournalJournal of the National Cancer Institute
Issue number4
Publication statusPublished - 1 Apr 2022

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© 2022 The Author(s) 2022. Published by Oxford University Press. All rights reserved.


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