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). Here, SMAD4 is linked to colorectal carcinoma.