In addition, combining SMAD3 with other hypomethylated genes, such as ACOT7, RASA3, B3GNTL1, PIGB, MAP3K5, LPIN1, and MYBPC3, which are potential biomarkers of CRC in the analytical model, may improve accuracy, increase sensitivity, and reduce false-positive results when predicting CRC in circulating methylated SMAD3. To confirm this, recruiting more patients with CRC and healthy participants is necessary. This evidence concerns the gene PIGB and colorectal carcinoma.