MADH4 (SMAD4), which encodes a component of the TGF-? growth-inhibitory signal transduction pathway, is inactivated in approximately 50% of pancreatic cancers, while mutations in SMAD2, another component of the pathway, are present in some colorectal tumors. Because of its association with pancreatic cancers, MADH4 (SMAD4) was originally designated DPC4, deleted in pancreatic cancer.

Pathology

 mutations of MADH4 in familial juvenile polyposis

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

 mutations of MADH4 in familial juvenile polyposis and hereditary haemorrhagic telangiectasia association (#15031030#)

• inactivation by mutations and deletions in 55% of pancreatic carcinomas
• colorectal carcinomas (inactivation of the Smad4 gene through homozygous deletion or intragenic mutation occurs frequently in association with malignant progression)

 mutation of this gene is seen only occasionally in the rest of human cancers.

• The majority of Smad4 gene mutations in human cancer are missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2), which interfere with the homo-oligomer formation of Smad4 protein and the hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGFbeta signaling.

See also: TGF-beta signaling pathway, TGF-beta signaling

References

 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#