Despite these notable findings, there are still some limitations in this study: (1) other potential targets of HAND2 such as PTEN signaling, and EGFR-RAS signaling need to be clarified; (2) the mechanism of HAND2 in binding to ERK and changes of downstream key molecules in ERK signaling need to be clarified in future study; (3) clinical application of HAND2 methylation and expression in early detection of CRC needed prospective trials. Here, HAND2 is linked to colorectal carcinoma.