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

Journal article

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% confidence interval: 1.80–6.11). In the TARGET-C trial, the PRS121 effectively distinguished patients with advanced neoplasia from controls (top 20%, odds ratio = 3.66). The PRS-based risk-adapted screening strategy improved AN detection compared with FIT-only screening, with higher sensitivity (69.4% vs. 54.1%, P = 7.6 × 10–4) and detection rate (16.7% vs. 13.1%, P = 0.024). Notably, PRS-based screening identified 21.1% of AN cases that were missed by FIT, and integrated risk stratification using PRS and APCS increased this proportion to 37.9%, demonstrating substantial improvement in detecting FIT-negative lesions. Conclusions: PRS enables effective risk stratification for colorectal cancer and improves detection of advanced neoplasia by identifying high-risk individuals missed by FIT, supporting its utility in precision risk-adapted screening. Trial registration: Chinese Clinical Trial Registry: ChiCTR1800015506. Registered on 4 April 2018.

Authors: Chen, H; Si, J; Luo, C; Tian, J; Xin, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Genome Medicine
• Volume: 18
• Issue: 1
• Article number: 48
• Publication date: 2026-03-19
• Acceptance date: 2026-03-06
• DOI: 10.1186/s13073-026-01623-z
• EISSN: 1756-994X
• ISSN: 1756-994X
• Language: English
• Keywords: Colorectal cancer; Polygenic risk score; Risk prediction; Precise screening