Abstract
BACKGROUND: Colorectal cancer (CRC) is the third-most-common malignancy and the second-leading cause of cancer-related deaths worldwide and current screening methods such as guaiac-based fecal occult blood test (gFOBT), fecal immunochemical test (FIT), and colonoscopy have their own pros and cons. This study aimed to assess the effectiveness of a fecal DNA methylation test by using methylated SDC2 (mSDC2) as the epigenetic biomarker for detecting CRC in a screening-naïve population. METHODS: Fecal mSDC2 test and FIT were simultaneously performed on eligible 40- to 74-year-old adults of a regional township in China. Subjects with positive results were recommended for colonoscopy. Data of positivity rates, positive predicted values (PPVs), and detection rates associated with clinical characteristics were analysed. RESULTS: The positivity rate of mSDC2 was 7.6% for 10,578 participants with valid results from both fecal mSDC2 test and FIT. With an adherence rate of 63.8% to colonoscopy referral, 25 CRCs, 189 advanced adenomas (AAs), and 165 non-advanced adenomas (NAAs) and polyps were detected. The PPVs of mSDC2 were 4.93%, 37.28%, and 32.54% for CRC, AA, and non-advanced lesions, respectively. When the CRCs and AAs were counted as positive findings, the fecal mSDC2 test showed a higher detective rate than FIT (relative risk [RR], 1.313 [1.129-1.528], P < 0.001). When NAAs and polyps were also specified as treatable lesions, the mSDC2 test was more effective in detecting these benign growths (RR, 1.872 [1.419-2.410]; P < 0.001). A combination of mSDC2 and FIT detected 29 CRCs, 298 AAs, and 234 NAAs and polyps. Overall, the fecal mSDC2 test had a higher detection rate for both advanced and non-advanced colonic lesions. The false-positive rate of the fecal mSDC2 test was comparable to that of FIT (RR, 1.169 [0.974-1.403]; P = 0.113). CONCLUSIONS: The single-target stool-based mSDC2 test can effectively and accurately detect CRC and precancerous lesions in a large-scale CRC-screening program. TRIAL REGISTRATION NUMBER: NCT05374369.