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SMAD4
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Interpretation 2308
Tier 2
SMAD4
Variants
SMAD4 R361C
Primary Sites
Ampulla (Pancreaticobiliary Duct)
Tumor Types
Adenocarcinoma
Interpretation

SMAD4 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ss signal transduction pathway. Germline mutations in SMAD4 have been associated with juvenile polyposis syndrome (JPS). Loss of SMAD4 expression or somatic mutations in SMAD4 are found in pancreatic cancer and are associated with tumor grade. Somatic alterations in SMAD4 are observed at lower frequencies in multiple tumor types, including colon and lung adenocarcinoma. SMAD4 R361C lies at a hotspot residue within MH2 domain of the Smad4 protein (UniProt.org). R361C confers a loss of function to the Smad4 protein as demonstrated by reduced Smad4 transactivating activity in cell assays. The SMAD4 R361C mutation is likely oncogenic. Studies of loss of function somatic mutations and studies of loss of heterozygosity (LOH) at the SMAD4 locus have shown an association with poor prognosis. There are ongoing clinical trials for colorectal tumors harboring SMAD4 alterations.

Citations
  1. Massague J. TGFb signalling in context. Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30.
  2. Kuang C, Chen Y. Tumor-derived C-terminal mutations of Smad4 with decreased DNA binding activity and enhanced intramolecular interaction. Oncogene. 2004 Feb 5;23(5):1021-9.
  3. Howe JR, Ringold JC, Summers RW, Mitros FA, Nishimura DY, Stone EM. A gene for familial juvenile polyposis maps to chromosome 18q21.1. Am J Hum Genet. 1998 May;62(5):1129-36.
  4. Fukushige S, Furukawa T, Satoh K, Sunamura M, Kobari M, Koizumi M, Horii A. Loss of chromosome 18q is an early event in pancreatic ductal tumorigenesis. Cancer Res. 1998 Oct 1;58(19):4222-6.
  5. Iacobuzio-Donahue CA, Fu B, Yachida S, Luo M, Abe H, Henderson CM, Vilardell F, Wang Z, Keller JW, Banerjee P, Herman JM, Cameron JL, Yeo CJ, Halushka MK, Eshleman JR, Raben M, Klein AP, Hruban RH, Hidalgo M, Laheru D. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009 Apr 10;27(11):1806-13.
  6. Miyaki M, Kuroki T. Role of Smad4 (DPC4) inactivation in human cancer. Biochem Biophys Res Commun. 2003 Jul 11;306(4):799-804.
  7. Yoshioka Y, Togashi Y, Chikugo T, Kogita A, Taguri M, Terashima M, Mizukami T,Hayashi H, Sakai K, de Velasco MA, Tomida S, Fujita Y, Tokoro T, Ito A, Okuno K, Nishio K. Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinomas. Cancer. 2015 Dec15;121(24):4359-68.
  8. Mehrvarz Sarshekeh A, et al. Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer. PLoS One. 2017 Mar 7;12(3):e0173345.
Last updated: 2019-01-22 18:42:00 UTC
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