We previously reported that nearly 65% of colon adenocarcinoma cases from the pan cancer cohort in The Cancer Genome Atlas (TCGA) exhibit alterations in TGF-β pathway genes (32), whereas mice with defects in TGF-β signaling (Sptbn1+/−Smad3+/− and Smad4+/−Sptbn1+/−) spontaneously developed adenomas and CRC (17, 33). This evidence concerns the gene SMAD4 and colon adenocarcinoma.