Loss of Function of SMAD4 in Cancer

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R-HSA-3304347
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Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
9506519 Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes

Takaku, K, Oshima, M, Miyoshi, H, Matsui, M, Seldin, MF, Taketo, MM

Cell 1998
10773876 Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice

Xu, X, Brodie, SG, Yang, X, Im, YH, Parks, WT, Chen, L, Zhou, YX, Weinstein, M, Kim, SJ, Deng, CX

Oncogene 2000
9214507 Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4

Hata, A, Lo, RS, Wotton, D, Lagna, G, Massagué, J

Nature 1997
9582123 Mutations in the SMAD4/DPC4 gene in juvenile polyposis

Howe, JR, Roth, S, Ringold, JC, Summers, RW, Järvinen, HJ, Sistonen, P, Tomlinson, IP, Houlston, RS, Bevan, S, Mitros, FA, Stone, EM, Aaltonen, LA

Science 1998
9214508 A structural basis for mutational inactivation of the tumour suppressor Smad4

Shi, Y, Hata, A, Lo, RS, Massagué, J, Pavletich, NP

Nature 1997
9990040 G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: phenotypes reversed by a tumorigenic mutation

Dai, JL, Bansal, RK, Kern, SE

Proc. Natl. Acad. Sci. U.S.A. 1999
23139211 SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer

Fleming, NI, Jorissen, RN, Mouradov, D, Christie, M, Sakthianandeswaren, A, Palmieri, M, Day, F, Li, S, Tsui, C, Lipton, L, Desai, J, Jones, IT, McLaughlin, S, Ward, RL, Hawkins, NJ, Ruszkiewicz, AR, Moore, J, Zhu, HJ, Mariadason, JM, Burgess, AW, Busam, D, Zhao, Q, Strausberg, RL, Gibbs, P, Sieber, OM

Cancer Res. 2013
20952405 COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer

Forbes, SA, Bindal, N, Bamford, S, Cole, C, Kok, CY, Beare, D, Jia, M, Shepherd, R, Leung, K, Menzies, A, Teague, JW, Campbell, PJ, Stratton, MR, Futreal, PA

Nucleic Acids Res. 2011
8553070 DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1

Hahn, SA, Schutte, M, Hoque, AT, Moskaluk, CA, da Costa, LT, Rozenblum, E, Weinstein, CL, Fischer, A, Yeo, CJ, Hruban, RH, Kern, SE

Science 1996
10436786 DPC4/SMAD4 gene alterations in human cancer, and their functional implications

Schutte, M

Ann. Oncol. 1999
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cancer 162 malignant tumor, malignant neoplasm, primary cancer
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