On the basis of comprehensive profiles of proximal/distal tumor locations, KRAS/BRAF mutations, and MLH1/RUNX3/SOCS1 methylation of serrated lesions, the major precursor of MLH1-methylated CIMP-H CRC may be SSA/P, whereas the major precursors of MLH1-unmethylated CIMP-H CRC may be KRAS-mutated TSA, followed by BRAF-mutated TSA and SSA/P (Figure 4A and 4B). This evidence concerns the gene RUNX3 and neoplasm.