SMAD4 was identified as a gene homozygously deleted in ~30% of pancreatic cancers and was named DPC4 (DPC stands for deleted in pancreatic cancer). SMAD4 maps to the chromosomal band 18q21.1, and about 90% of pancreatic carcinomas show allelic loss at chromosomal arm 18q (Hahn et al. 1996), while ~50% of pancreatic cancers show some alteration of the SMAD4 gene (reviewed by Schutte et al. 1999).
Based on COSMIC database (Catalogue Of Somatic Mutations In Cancer) (Forbes et al. 2011), mutations in the coding sequence of SMAD4 gene are frequently found in pancreatic cancer, biliary duct carcinoma and colorectal cancer (reviewed by Schutte et al. 1999). Germline SMAD4 mutations are the cause of juvenile polyposis, an autosomal dominant disease that predisposes affected individuals to hamartomatous polyps and gastrointestinal cancer (Howe et al. 1998). Homozygous Smad4 loss is embryonic lethal in mice (Takaku et al. 1998). Smad4 +/- heterozygotes appear normal but develop intestinal polyps between 6 and12 months of age and these polyps can progress to cancer. Loss of the remaining wild-type Smad4 allele is detectable only at later stages of tumor progression in Smad4+/- mice (Xu et al. 2000). Compound Apc+/-;Smad4+/- mice develop malignant tumors from intestinal polyps more rapidly than Apc+/- mice (Takaku et al. 1998).
SMAD4 coding sequence mutations are most frequently found in the MH2 domain and impair the formation of SMAD4 heterotrimers with phosphorylated SMAD2 and SMAD3 (Shi et al. 1997, Fleming et al. 2013), thereby impairing SMAD4:SMAD2/3 heterotrimer-mediated transcriptional regulation of TGF-beta responsive genes. MH2 domain is also involved in the formation of SMAD4 homotrimers which may play a role in SMAD4 protein stability (Shi et al. 1997).
Coding sequence mutations are also found in the MH1 domain of SMAD4. MH1 domain is involved in DNA binding (Dai et al. 1999) and it is also involved in the formation of SMAD4 homotrimers (Hata et al. 1997).