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SMAD4
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Interpretation 2302
Tier 2
SMAD4
Variants
SMAD4 D351G
Primary Sites
Pancreas
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. SMAD4 is mutated in one third of colorectal cancer and half of pancreatic tumors. Genetic alterations in SMAD4 have been identified in 33% of pancreatic adenocarcinomas. SMAD4 inactivation by allelic deletion or mutation mainly occurs in late stage pancreatic ductal adenocarcinoma and is associated with poorer prognosis. SMAD4 D351G lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org). D351G has been identified in sequencing studies, but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown. The SMAD4 D351H variant has been described in human colorectal cancer cell lines and reported as likely oncogenic, suggesting that the D351G variant is also likely to be oncogenic. SMAD4 loss has been found to increase resistance to the chemotherapeutic agent 5'-fluorouracil.

Citations
  1. Massague J. TGFb signalling in context. Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30.
  2. 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.
  3. Comprehensive TCGA PanCanAtlas (https://gdc.cancer.gov/about-data/publications/pancanatlas).
  4. Chen et al. SMAD4 Loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells. BMC Cancer 2014, 14:181
  5. 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. SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Res. 2013 Jan 15;73(2):725-35.
  6. Lee S, Lee J, Sim SH, Lee Y, Moon KC, Lee C, Park WY, Kim NK, Lee SH, Lee H.
  7. Comprehensive somatic genome alterations of urachal carcinoma. J Med Genet. 2017 Aug;54(8):572-578.
  8. Vinayanuwattikun C, Le Calvez-Kelm F, Abedi-Ardekani B, Zaridze D, Mukeria A,
  9. Voegele C, Vallee M, Purnomosari D, Forey N, Durand G, Byrnes G, Mckay J, Brennan P, Scelo G. Elucidating Genomic Characteristics of Lung Cancer Progression from In Situ to Invasive Adenocarcinoma. Sci Rep. 2016 Aug 22;6:31628.
  10. De Bosscher K, Hill CS, Nicolas FJ. Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells. Biochem J. 2004;379(Pt 1):209-16.
Last updated: 2019-01-22 18:39:52 UTC
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