e15541 Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by regulating cell adhesion, tissue differentiation and angiogenesis. The aim of this study is to verify the sensitivity and specificity of fecal SDC2 gene methylation in the detection of colorectal cancer, find the dominant population who can benefit from this detection, expand its clinical application scenarios, and explore its role in the evaluation of the efficacy and prognosis of patients with advanced colorectal cancer. Methods: A total of 72 patients diagnosed with colorectal cancer were included in the study. The methylation level of SDC2 gene in feces of patients was detected by fluorescence PCR. We evaluated sensitivity and specificity and assessed associations between fecal SDC2 methylation levels, fecal occult blood tests, characteristics of the lesions on colonoscopy, and clinical practice. The critical value of reaction solution A was 10.0, and the critical value of reaction solution B was 10.5. When the Ct value of any tube of reaction solution A or B was less than the critical value, it was judged as "positive". Results: Data from 72 patients were evaluated, with a sensitivity of 89.1% (41/46 95%CI 0.798 to 0.985) for patients with untreated colorectal cancer. The sensitivity of SDC2 methylation detection was 46.2% (12/26 95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference in the detection rate of SDC2 methylation between the two groups was statistically significant (P < 0.001). Among the 46 untreated patients with colorectal cancer, 32 patients with positive SDC2 gene methylation received radical surgery, and 30 of them (93.75%) turned to SDC2 gene methylation negative after surgery. Patients who achieved clinical benefit (CR+PR+SD) found reduced SDC2 gene methylation levels in the stool.There was no significant difference in the methylation level of SDC2 gene between colorectal cancer patients with different fecal occult blood test results (-, +, ++, +++) (P = 0.564)、different lesions (ascending colon, transverse colon , descending colon , sigmoid colon, and rectal) (P = 0.179)、different stages (stage I, II, III, IV) (P = 0.828)、different types (infiltrative, ulcerative, protruding) (P = 0.629), and different sizes of lesions (≤ 5cm, 6-9cm, ≥10cm) (P = 0.644). Conclusions: The high sensitivity of fecal SDC2 gene methylation in detecting untreated CRC patients may help make colonoscopy a screening method only for those at high risk of developing CRC. It may help to evaluate the efficacy of radical surgery, predict the recurrence of colorectal cancer and monitor the efficacy of palliative treatments for colorectal cancer. This work was supported by Shanghai Shenkang Project (No.SHDC2022CRT009).