SMAD4 encodes a member of the Smad family
of signal transduction proteins. Smad4 acts as an intracellular mediator of
and activin type 1 receptor, to regulate cell growth and differentiation.
Somatic mutations in SMAD4 appear frequent
in pancreatic, colorectal, upper aerodigestive tract, thyroid, biliary tract
cancers. About one half of these mutations are substitutions. No specific
mutation hot spot has been identified. Mutant Smad4 proteins, identified in
human carcinomas, were found to be impaired in their ability to regulate gene
alterations of SMAD4 are a cause of juvenile polyposis syndrome (JPS or JP).
JPS is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome
in which patients are at risk for developing gastrointestinal cancers. Defects
in SMAD4 may also be observed in some patients with juvenile
polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT), in which JP
and hereditary hemorrhagic telangiectasia (HHT) coexist in a single individual.
Both JIP and HHT are autosomal dominant disorders, but with distinct and
non-overlapping clinical features. HHT is a vascular malformation disorder.
References (open access):
Juvenile Polyposis Syndrome. Larsen Haidle
J, Howe JR. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
SourceGeneReviews [Internet]. Seattle (WA): University of Washington, Seattle;
1993-.2003 May 13 [updated 2008 Sep 09].
SMAD4 gene mutations are associated with
poor prognosis in pancreatic cancer. Blackford A, Serrano OK, Wolfgang CL,
Parmigiani G, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR,
Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Cameron JL, Olino K,
Schulick R, Winter J, Herman JM, Laheru D, Klein AP, Vogelstein B, Kinzler KW,
Velculescu VE, Hruban RH. Clin Cancer Res. 2009 Jul 15;15(14):4674-9.