Home > A. Molecular pathology > MADH4



Monday 8 December 2003

Definition: The tumor suppressor gene Smad4 (MADH4, DPC4) at chromosome 18q21.1 belongs to the Smad family, which mediates the TGFbeta signaling pathway suppressing epithelial cell growth. (MIM. 600993)

SMAD4 (MADH4) encodes a component of the TGF-alpha growth-inhibitory signal transduction pathway. The tumor suppressor function of SMAD4 lies in its capacity to mediate the effects of transforming growth factor–â superfamily signaling.


- germline mutations of SMAD4 in familial juvenile polyposis

  • polyps are formed by inactivation of the Smad4 gene through germline mutation and loss of the unaffected wild-type allele.

- germline mutations of SMAD4 in familial juvenile polyposis and hereditary haemorrhagic telangiectasia association (JP-HHT syndrome) (#15031030#)

- inactivation by somatic mutations and somatic deletions in 55% of pancreatic carcinomas

- somatic inactivation in colorectal carcinomas

  • inactivation of the SMAD4 gene through homozygous deletion or intragenic mutation occurs frequently in association with malignant progression)
  • In primary colorectal tumors, loss of E-cadherin is highly correlated with loss of SMAD4.
  • Furthermore, in small intestinal adenocarcinomas, inactivating mutations of the SMAD4 gene have been observed.

- SMAD4 (MADH4) is inactivated in approximately 50% of pancreatic cancers.

  • Because of its association with pancreatic cancers, MADH4 (SMAD4) was originally designated DPC4, deleted in pancreatic cancer.

- somatic mutation in other human cancers

  • missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2),
    • interference with the homo-oligomer formation of Smad4 protein and the hetero-oligomer formation between SMAD4 and Smad2 proteins, resulting in disruption of TGFbeta signaling.

- Loss of Dpc4 (SMAD4) expression provides the most useful immunohistochemical evidence for establishing the pancreaticobiliary tract as the most likely source of these metastatic mucinous carcinomas in the ovary. (#21263249#)

See also

- TGF-beta signaling pathway (TGF-beta signaling)


- Ovarian metastases of pancreaticobiliary tract adenocarcinomas: analysis of 35 cases, with emphasis on the ability of metastases to simulate primary ovarian mucinous tumors. Meriden Z, Yemelyanova AV, Vang R, Ronnett BM. Am J Surg Pathol. 2011 Feb;35(2):276-88.PMID: #21263249#

- Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004 Mar 13;363(9412):852-9.
PMID: #15031030#

- Miyaki M, Kuroki T. Role of Smad4 (DPC4) inactivation in human cancer. Biochem Biophys Res Commun. 2003 Jul 11;306(4):799-804. PMID: #12821112#


  • Juvenile polyps in juvenile polyposis
  • TDGF1-MADH4 (SMAD4) signaling pathway