Indeed, the loss of BMPR2 and SMAD4 expression has been reported in sporadic CRC, whereas germline mutations of BMPR1 and SMAD4 genes have been demonstrated to enhance the susceptibility to develop juvenile polyposis, supporting that TGF-β signaling inactivation plays a key role in CRC development [18–22]. Here, SMAD4 is linked to juvenile polyposis syndrome.