Risk Stratification for Early-Onset Colorectal Cancer Using a Combination of Genetic and Environmental Risk Scores

An International Multi-Center Study

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


J Natl Cancer Inst. 2022;114(4):528-539. 

In This Article

Abstract and Introduction

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.


The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years (early-onset CRC) has been on the rise for the last several decades in the United States and several other countries.[1–4] Early-onset CRC often presents at an advanced stage because of diagnostic delay and aggressive pathology,[5] making earlier detection of susceptible individuals a high priority. In response to this increasing public health challenge, the American Cancer Society, the US Preventative Services Task Force, and the American College of Gastroenterology have recently made recommendations regarding lowering the screening age to younger than 50 years.[6–8] However, other professional bodies still recommend a starting age for CRC screening at 50 years,[9,10] whereas the US Multi-Society Task Force on Colorectal Cancer suggests a screening age of 45 years only for African Americans.[11]

Although advocates for initiating screening at an earlier age propose that the benefits of life-years gained outweigh the concerns about unnecessary invasive procedures and associated costs, others suggest, given the extremely low absolute risk of cancer among persons younger than age 50 years, that more targeted approaches for individuals at higher risk are warranted, especially for the use of invasive methods such as colonoscopy.[12,13] By using a combination of environmental and lifestyle risk factors and germline genetic variants, precision cancer screening may allow for improved risk discrimination and subsequent gains in the benefit-to-harm ratio compared with more traditional age-based screening regimens.[14–18] To date, our risk prediction models for early-onset CRC have focused on genetic factors;[16] thus, additional risk assessment incorporating environmental and lifestyle factors should be explored in conjunction with germline genetics.

In this study, we used data from 13 population-based studies, including 3486 cases and 3890 controls, to construct risk prediction models for early-onset CRC that incorporate a novel aggregate environmental risk score (ERS) and a recently expanded polygenic risk score (PRS),[15] now including 141 common genetic variants. We additionally evaluated the absolute risks of early-onset CRC across risk factor profiles of the ERS and PRS. The findings of this study may contribute towards identifying high-risk populations that may benefit from personalized preventive interventions for early-onset CRC.