Journal Article

DKFZ-2023-00065

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Validation of a genetic-enhanced risk prediction model for colorectal cancer in a large community-based cohort.

Su, Y.-R. ; Sakoda, L. C. ; Jeon, J. ; Thomas, M. ; Lin, Y. ; Schneider, J. L. ; Udaltsova, N. ; Lee, J. K. ; Lansdorp-Vogelaar, I. ; Peterse, E. F. P. ; Zauber, A. G. ; Zheng, J. ; Zheng, Y. ; Hauser, E. ; Baron, J. A. ; Barry, E. L. ; Bishop, D. T. ; Brenner, H.DKFZ* ; Buchanan, D. D. ; Burnett-Hartman, A. ; Campbell, P. T. ; Casey, G. ; Castellví-Bel, S. ; Chan, A. T. ; Chang-Claude, J.DKFZ* ; Figueiredo, J. C. ; Gallinger, S. J. ; Giles, G. G. ; Gruber, S. B. ; Gsur, A. ; Gunter, M. J. ; Hampe, J. ; Hampel, H. ; Harrison, T. A. ; Hoffmeister, M.DKFZ* ; Hua, X. ; Huyghe, J. R. ; Jenkins, M. A. ; Keku, T. O. ; Le Marchand, L. ; Li, L. ; Lindblom, A. ; Moreno, V. ; Newcomb, P. A. ; Pharoah, P. D. P. ; Platz, E. A. ; Potter, J. D. ; Qu, C. ; Rennert, G. ; Schoen, R. E. ; Slattery, M. L. ; Song, M. ; van Duijnhoven, F. J. B. ; Van Guelpen, B. ; Vodicka, P. ; Wolk, A. ; Woods, M. O. ; Wu, A. H. ; Hayes, R. B. ; Peters, U. ; Corley, D. A. ; Hsu, L.

2023
AACR Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1158/1055-9965.EPI-22-0817

Abstract: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer (CRC) screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced CRC risk model comprising 140 known CRC loci to provide a comprehensive assessment on prediction performance.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 CRC 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 45-74 years (screening-eligible age group) and 40-49 years with no endoscopy history (younger-age group).In European-ancestral individuals, the predicted 5-year risk calibrated well (E/O=1.01 (95%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-value<0.001) and 0.14 (p-value=0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER CRC-incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (p-value<0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (p-value=0.04) with similar specificity.The proposed PRS-enhanced model provides a well-calibrated 5-year CRC risk prediction and improves discriminatory accuracy in the external cohort.The proposed model has potential utility in risk-stratified CRC prevention.

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)
2. C020 Epidemiologie von Krebs (C020)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF < 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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