SMAD4 (also known as DPC4) was identified on the basis of frequent homozygous deletions and mutations44, serves as the central mediator of TGF-β/SMADs signaling and functions as a tumor suppressor with over 50% of SMAD4 loss or inactivation in PDAC45,46, among which homozygous deletion and inactivation of SMAD4 were found in ~30% and 20% of pancreatic cancer patients, respectively. Here, SMAD4 is linked to familial pancreatic carcinoma.