Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort
Authors: Su Yu-Ru , Sakoda Lori C. , Jeon Jihyoun , Thomas Minta , Lin Yi , Schneider Jennifer L. , Udaltsova Natalia , Lee Jeffrey K. , Lansdorp-Vogelaar Iris , Peterse Elisabeth F.P. , Zauber Ann G. , Zheng Jiayin , Zheng Yingye , Hauser Elizabeth , Baron John A. , Barry Elizabeth L. , Bishop D. Timothy , Brenner Hermann , Buchanan Daniel D. , Burnett-Hartman Andrea , Campbell Peter T. , Casey Graham , Castellví-Bel Sergi , Chan Andrew T. , Chang-Claude Jenny , Figueiredo Jane C. , Gallinger Steven J. , Giles Graham G. , Gruber Stephen B. , Gsur Andrea , Gunter Marc J. , Hampe Jochen , Hampel Heather , Harrison Tabitha A. , Hoffmeister Michael , Hua Xinwei , Huyghe Jeroen R. , Jenkins Mark A. , Keku Temitope O. , Marchand Loic Le , Li Li , Lindblom Annika , Moreno Victor , Newcomb Polly A. , Pharoah Paul D.P. , Platz Elizabeth A. , Potter John D. , Qu Conghui , Rennert Gad , Schoen Robert E. , Slattery Martha L. , Song Mingyang , van Duijnhoven Fränzel J.B. , Van Guelpen Bethany , Vodicka Pavel , Wolk Alicja , Woods Michael O. , Wu Anna H. , Hayes Richard B. , Peters Ulrike , Corley Douglas A. , Hsu Li 
Published: January 2023

AbstractBackground:Polygenic risk scores (PRS) which summarize individuals’ genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance.Methods:The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group).Results:In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91–1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71–0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P &lt; 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P &lt; 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity.Conclusions:The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort.Impact:The proposed model has potential utility in risk-stratified colorectal cancer prevention.