A Validation Study of Methylated Syndecan-2 in Stool DNA for the Detection of Colorectal Cancer

Background/Objectives: The stool DNA-based SDC2 methylation (meSDC2) test has emerged as a promising noninvasive tool for the early detection of colorectal cancer (CRC). This study aimed to validate the clinical performance of the meSDC2 test for CRC detection in a multicenter hospital setting. Materials and Methods: This prospective, retrospective, multicenter, single-blind, case-control study was conducted at three tertiary medical centers. The primary endpoints were sensitivity and specificity for CRC detection. Secondary endpoints included test performance by tumor stage and location, and positivity rates in non-CRC lesions. Results: Among 636 participants, 260 (40.9%) had CRC, 173 (27.2%) had colorectal polyps, and 182 (28.6%) had normal colonoscopy findings. The meSDC2 test demonstrated a sensitivity of 87.7% (95% CI: 83.7-91.7%) and a specificity of 86.2% (95% CI: 82.7-89.7%) for CRC detection, with an AUC of 0.869 (95% CI: 0.841-0.895). Specificity among participants with negative colonoscopy findings was 91.8%. Positivity rates were 28.3% (95% CI: 15.3-41.3%) for advanced adenomas and 13.8% (95% CI: 6.6-21.0%) for non-advanced adenomas. Compared with the fecal immunochemical test (FIT), the meSDC2 test showed significantly higher sensitivity, whereas FIT demonstrated higher specificity. Combined testing improved sensitivity to 95.6% and 82.4% specificity. The meSDC2 test also showed significantly greater sensitivity than FIT for early-stage CRC (p = 0.037), while combined testing further improved sensitivity for both early- and late-stage CRC(p = 0.037 and p = 0.006, respectively). Conclusions: The stool-based meSDC2 test demonstrated high sensitivity, specificity, and consistent diagnostic performance across subgroups, supporting its clinical utility as a reliable and noninvasive CRC screening tool.