18q21.2

DPC4,JIP,MADH4,MYHRS

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Juvenile polyposis and hereditary hemorrhagic telangiectasia syndrome is an autosomal dominant disorder with distinct clinical features. One form corresponding to a predisposition to gastrointestinal polyps and cancer may be associated with mutations in Smad4 gene.

Polyps are formed by inactivation of the Smad4 gene through germline mutations and loss of the unaffected wild-type allele.

Pancreatic carcinoma

90% of pancreatic carcinomas show allelic loss at 18q. A consensus region of homozygous deletion at 18q21.1 was found in one third of pancreatic carcinomas and intragenic mutations were found in another 20% of this tumor type.

Smad4 expression may be a molecular prognostic marker for pancreatic carcinoma. A lower patient survival may be associated with loss of Smad4 expression.

Smad4 was proposed to be a tumor suppressor gene that may function to disrupt TGF-beta signaling. Mutant Smad4 proteins, identified in human carcinomas, were found to be impaired in their ability to regulate gene transcription. Most 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 hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGF-beta signaling.