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)
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.
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