The sequential genetic alterations of APC, KRAS, SMAD4, and TP53 could recapitulate the key features in transition from normal to adenoma and to initiation and progression of CRC, which promoted the understanding of pathogenesis in CRCs (Powell et al., 1992; Drost et al., 2015; Chen et al., 2016). Here, SMAD4 is linked to adenoma.