Effectiveness of single-target fecal DNA methylation test in regional mass screening for colorectal cancer and precancerous lesions in China

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.