Among them, the machine learning-driven five-gene diagnostic model (S100A11/CA4/PDCD4/GSTM2/SORD) demonstrated performance beyond the existing single-marker detection system in cross-cohort validation, with an AUC value of 0.965, which provides a new paradigm for the non-invasive diagnosis of early colorectal cancer. This evidence concerns the gene CA4 and colorectal cancer.