Optimizing colorectal cancer screening through polygenic risk score-based risk stratification: evidence from a population-based cohort and screening trial

作者：Hongda Chen, Jiahui Si, Chenyu Luo, Jianbo Tian, Junyi Xin, Canqing Yu, Dianjianyi Sun, Pei Pei, Ling Yang, Iona Y. Millwood, Robin G. Walters, Yiping Chen, Huaidong Du, Zhengming Chen, Liming Li, Masaru Koido, Yoichiro Kamatani, Meilin Wang, Xiaoping Miao, Jiayi Lv, Min Dai · 发表于：Genome Medicine · 年份：2026 · DOI：10.1186/s13073-026-01623-z · 被引用次数：1 · 研究领域：Colorectal Cancer Screening and Detection、Genetic Associations and Epidemiology、Genetic factors in colorectal cancer

BACKGROUND: Accurate risk stratification of colorectal cancer (CRC) is essential for precise screening. Polygenic risk scores (PRS) hold promise for improving predictive efficacy in CRC. However, the real-world applicability of a risk-adapted CRC screening strategy based on the PRS remains underexplored. Therefore, we aimed to evaluate the optimized PRS in a large prospective cohort in China and assess its utility for risk-adapted CRC screening. METHODS: We evaluated multiple PRS construction strategies using East Asian genome-wide association study data and well-established PRSs to select an optimal score, which was then assessed in 100,639 eligible participants from the China Kadoorie Biobank. The risk-adapted screening strategy assigns high-risk individuals to colonoscopy and low-risk individuals to fecal immunochemical testing (FIT), with FIT-positive cases referred for colonoscopy. We assessed the screening performance of the PRS, Asia–Pacific Colorectal Screening score, and their combination-based risk-adapted screening strategies against a standard FIT-based strategy among 2,821 participants in the TARGET-C CRC screening trial. RESULTS: The combined PRS (i.e., PRS121) demonstrated the best predictive performance (C-index = 0.602) for CRC. Individuals in the highest PRS quintile (top 20%) exhibited a 2.69-fold increased CRC risk compared with those in the lowest quintile. The high PRS and unfavorable lifestyle group conferred the highest risk (hazard ratio = 3.32, 95% c...