Mothers against decapentaplegic homolog 4 (SMAD4) is the central mediator of TGF-β signaling; its mutations have been identified in CRC and it is associated mainly with colon cancer (rather than rectal cancer), female sex, and shorter OS than wt SMAD4 CRC patients (mOS 29 months vs. 56 months) [141]. This evidence concerns the gene SMAD4 and rectal cancer.