SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer

Fleming, Nicholas I., Jorissen, Robert N., Mouradov, Dmitri, Christie, Michael, Sakthianandeswaren, Anuratha, Palmieri, Michelle, Day, Fiona, Li, Shan, Tsui, Cary, Lipton, Lara, Desai, Jayesh, Jones, Ian T., McLaughlin, Stephen, Ward, Robyn L., Hawkins, Nicholas J., Ruszkiewicz, Andrew R., Moore, James, Zhu, Hong-Jian, Mariadason, John M., Burgess, Antony W., Busam, Dana, Zhao, Qi, Strausberg, Robert L., Gibbs, Peter and Sieber, Oliver M. (2013) SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Research, 73 2: 725-735. doi:10.1158/0008-5472.CAN-12-2706


Author Fleming, Nicholas I.
Jorissen, Robert N.
Mouradov, Dmitri
Christie, Michael
Sakthianandeswaren, Anuratha
Palmieri, Michelle
Day, Fiona
Li, Shan
Tsui, Cary
Lipton, Lara
Desai, Jayesh
Jones, Ian T.
McLaughlin, Stephen
Ward, Robyn L.
Hawkins, Nicholas J.
Ruszkiewicz, Andrew R.
Moore, James
Zhu, Hong-Jian
Mariadason, John M.
Burgess, Antony W.
Busam, Dana
Zhao, Qi
Strausberg, Robert L.
Gibbs, Peter
Sieber, Oliver M.
Title SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
Publication date 2013-01-15
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-12-2706
Volume 73
Issue 2
Start page 725
End page 735
Total pages 11
Language eng
Subject 1306 Cancer Research
2730 Oncology
Abstract Activation of the canonical TGF-β signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2, and SMAD3 and analyzed for allelic loss by single-nucleotide polymorphism (SNP) microarray analysis. Mutation spectra were compared between the genes, the pathogenicity of mutations was assessed, and relationships with clinicopathologic features were examined. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. A significant overrepresentation of two genetic hits was detected for SMAD4 and SMAD3, consistent with these genes acting as tumor suppressors. SMAD4 mutations were associated with mucinous histology. The mutation spectra of SMAD2 and SMAD3 were highly similar to that of SMAD4, both in mutation type and location within the encoded proteins. In silico analyses suggested the majority of the mutations were pathogenic, with most missense changes predicted to reduce protein stability or hinder SMAD complex formation. The latter altered interface residues or disrupted the phosphorylation-regulated Ser-Ser-XSer motifs within SMAD2 and SMAD3. Functional analyses of selected mutations showed reductions in SMAD3 transcriptional activity and SMAD2-SMAD4 complex formation. Joint biallelic hits in SMAD2 and SMAD3 were overrepresented and mutually exclusive to SMAD4 mutation, underlining the critical roles of these three proteins within the TGF-β signaling pathway.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Tue, 10 Feb 2015, 13:14:16 EST by Ms Kate Rowe on behalf of School of Medicine