Validation of a genetic-enhanced risk prediction model for colorectal cancer in a large community-based cohort.
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States.
- Kaiser Permanente Northern California, Oakland, CA, United States.
- University of Michigan-Ann Arbor, Ann Arbor, Michigan, United States.
- Fred Hutchinson Cancer Research Center, Seattle, United States.
- Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
- Kaiser Permanante Northern California, oakland, CA, United States.
- Kaiser Permanente Northern California, Oakland, California, United States.
- Erasmus MC, Rotterdam, Netherlands.
- Memorial Sloan Kettering Cancer Center, New York, NY, United States.
- Fred Hutchinson Cancer Research Center, United States.
- VA Cooperative Studies Program Epidemiology Center, Durham Veterans Affairs Health Care System, Durham, NC, United States.
- University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
- Geisel School of Medicine at Dartmouth College, Lebanon, NH, United States.
- University of Leeds, Leeds, West Yorkshire, United Kingdom.
- German Cancer Research Center, Heidelberg, Germany.
- University of Melbourne, Parkville, Victoria, Australia.
- Kaiser Permanente Colorado, Aurora, CO, United States.
- Albert Einstein College of Medicine, Bronx, NY, United States.
- University of Virginia, Charlottesville, United States.
- IDIBAPS, Barcelona, Spain.
- Massachusetts General Hospital, Boston, MA, United States.
- Cedars-Sinai Medical Center Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, United States.
- University Health Network, Canada.
- Cancer Council Victoria, Melbourne, VIC, Australia.
- City of Hope National Medical Center Center for Precision Medicine, Duarte, CA, United States.
- Medical University of Vienna, Vienna, Austria.
- International Agency For Research On Cancer, Lyon Cedex 08, France.
- University Hospital Dresden, Dresden, Germany.
- The Ohio State University, Columbus, Ohio, United States.
- Fred Hutchinson Cancer Center, Seattle, United States.
- University of Melbourne, Victoria, Victoria, Australia.
- University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
- University of Hawaii Cancer Center, Honolulu, Hawaii, United States.
- Case Western Reserve University, Cleveland, United States.
- Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
- Catalan Institute of Oncology, Hopitalet de Llobregat, Barcelona, Spain.
- Cedars-Sinai Medical Center, West Hollywood, CA, United States.
- Johns Hopkins Bloomberg School of Public Health, Baltimore, United States.
- Massey University, Wellington, New Zealand.
- Carmel Medical Center and Faculty of Medicine, Technion, Haifa, Israel.
- University of Pittsburgh Medical Center, Pittsburgh, PA, United States.
- University of Utah Health Sciences Center, Salt Lake City, Utah, United States.
- Harvard T.H. Chan School of Public Health, Boston, MA, United States.
- Wageningen University & Research, Wageningen, Netherlands.
- Umeå University, Umeå, Sweden.
- Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
- Karolinska Institute, Stockholm, Sweden.
- Memorial University of Newfoundland, St. John's, NL, Canada.
- University of Southern California, Los Angeles, California, United States.
- New York University School of Medicine, New York, NY, United States.
- Kaiser Permanente Southern California, Oakland, CA, United States.
BACKGROUND: 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.
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 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).
RESULTS: 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.
CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year CRC risk prediction and improves discriminatory accuracy in the external cohort.
IMPACT: The proposed model has potential utility in risk-stratified CRC prevention.
- 2014-0244: Colorectal Tumor Risk Prediction in the PLCO Trial (ULRIKE PETERS)