Comparison of stool DNA–based SDC2 methylation testing and repeat fit for advanced colorectal neoplasia in fit-positive individuals: a multicenter prospective exploratory study

Abstract Background and Aim Fecal immunochemical test (FIT)–based colorectal cancer (CRC) screening is limited by false-negatives due to bleeding dependence and a high false-positive burden. We compared the diagnostic accuracy of stool DNA–based SDC2 methylation testing versus repeat FIT for detecting advanced colorectal neoplasia (ACN) in FIT-positive individuals. Methods In this multicenter prospective exploratory study, adults aged ≥ 40 years with a positive FIT (≥ 100 ng/mL) underwent colonoscopy. Pre-colonoscopy stool samples were analyzed using a stool DNA–based SDC2 methylation assay and a repeat FIT. Diagnostic performance for ACN was compared with repeat FIT, using colonoscopy as the reference standard. Results Among 82 participants, 20 (24.4%) had ACN, including 7 CRC cases. In the full cohort (20 ACN vs. 62 non-ACN), SDC2 methylation testing showed numerically higher sensitivity for ACN than repeat FIT (70.0% vs. 45.0%) with a lower false-negative rate (30.0% vs. 55.0%), whereas repeat FIT showed higher specificity (96.8% vs. 80.6%). On paired testing, the sensitivity difference was not statistically significant (exact McNemar P = 0.125), whereas the higher specificity of repeat FIT was significant ( P = 0.013). Diagnostic accuracy was 78.0% for SDC2 methylation testing and 84.1% for repeat FIT. Conclusions In FIT-positive individuals, SDC2 methylation testing showed numerically higher sensitivity for advanced neoplasia than repeat FIT but lower specificity, and the sensitivity difference was not statistically significant. The lower specificity limits its utility as a triage tool, and these findings do not support using SDC2 testing to select patients for, or to withhold, colonoscopy after a positive FIT. Larger studies are needed to define its role in this setting. Trial registration Clinical Research Information Service (CRIS), Republic of Korea; KCT0010882; registered on August 12, 2025.