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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer

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Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort.

Yu-Ru Su^1,2, Lori C Sakoda^2,3,4, Jihyoun Jeon⁵

¹Biostatistics Unit, Kaiser Permanente Washington Health Research Institute, Seattle, Washington.

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology

|January 9, 2023

Summary

Polygenic risk scores (PRS) enhance colorectal cancer risk prediction. External validation shows the PRS-enhanced model improves accuracy and aids in targeted screening strategies for better prevention.

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Area of Science:

Genetics and Genomics
Cancer Epidemiology
Preventive Medicine

Background:

Polygenic risk scores (PRS) can summarize genetic predisposition to colorectal cancer (CRC).
External validation of PRS-enhanced CRC risk models in large cohorts is crucial for clinical implementation.
This study assessed a PRS-enhanced CRC risk model using 140 CRC loci.

Purpose of the Study:

To externally validate a PRS-enhanced colorectal cancer risk model.
To assess the model's prediction performance, including calibration and discriminatory accuracy.
To evaluate the impact of PRS on risk prediction in different age groups.

Main Methods:

The PRS model was developed in 20,338 individuals and validated in a 85,221-person community cohort.
5-year absolute CRC risk was validated using calibration (E/O ratios) and discrimination (time-dependent AUC).
PRS impact on AUC, sensitivity, and specificity was assessed in screening-eligible (45-74 yrs) and younger (40-49 yrs) age groups.

Main Results:

The PRS-enhanced model demonstrated good calibration (E/O=1.01) and high discriminatory accuracy (AUC=0.73) in European-ancestry individuals.
Adding PRS improved 5-year AUC by 0.06 in screening-eligible and 0.14 in younger individuals.
PRS improved specificity by 11% in screening-eligible and sensitivity by 27% in younger individuals.

Conclusions:

The PRS-enhanced model offers well-calibrated 5-year CRC risk prediction.
The model significantly improves discriminatory accuracy in an external validation cohort.
This PRS-enhanced model shows potential for risk-stratified colorectal cancer prevention strategies.