SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer

Nicholas I. Fleming, Robert Jorissen, Dmitri Mouradov, Michael Christie, Anuratha Sakthianandeswaren, Michelle Palmieri, Fiona Day, Shan Li, Cary Tsui, Lara Lipton, Jayesh Desai, Ian T. Jones, Stephen McLaughlin, Robyn L. Ward, Nicholas J. Hawkins, Andrew R. Ruszkiewicz, James Moore, Hong Jian Zhu, John M. Mariadason, Antony W. Burgess & 5 others Dana Busam, Qi Zhao, Robert L. Strausberg, Peter Gibbs, Oliver M. Sieber

Research output: Contribution to journalArticle

134 Citations (Scopus)

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.

LanguageEnglish
Pages725-735
Number of pages11
JournalCancer Research
Volume73
Issue number2
DOIs
Publication statusPublished - 15 Jan 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Fleming, N. I., Jorissen, R., Mouradov, D., Christie, M., Sakthianandeswaren, A., Palmieri, M., ... Sieber, O. M. (2013). SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Research, 73(2), 725-735. https://doi.org/10.1158/0008-5472.CAN-12-2706
Fleming, Nicholas I. ; Jorissen, Robert ; 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. / SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. In: Cancer Research. 2013 ; Vol. 73, No. 2. pp. 725-735.
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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.",
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Fleming, NI, Jorissen, R, 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 2013, 'SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer', Cancer Research, vol. 73, no. 2, pp. 725-735. https://doi.org/10.1158/0008-5472.CAN-12-2706

SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. / Fleming, Nicholas I.; Jorissen, Robert; 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.

In: Cancer Research, Vol. 73, No. 2, 15.01.2013, p. 725-735.

Research output: Contribution to journalArticle

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AU - Fleming, Nicholas I.

AU - Jorissen, Robert

AU - Mouradov, Dmitri

AU - Christie, Michael

AU - Sakthianandeswaren, Anuratha

AU - Palmieri, Michelle

AU - Day, Fiona

AU - Li, Shan

AU - Tsui, Cary

AU - Lipton, Lara

AU - Desai, Jayesh

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AU - McLaughlin, Stephen

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AU - Hawkins, Nicholas J.

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AU - Mariadason, John M.

AU - Burgess, Antony W.

AU - Busam, Dana

AU - Zhao, Qi

AU - Strausberg, Robert L.

AU - Gibbs, Peter

AU - Sieber, Oliver M.

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AB - 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.

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Fleming NI, Jorissen R, Mouradov D, Christie M, Sakthianandeswaren A, Palmieri M et al. SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Research. 2013 Jan 15;73(2):725-735. https://doi.org/10.1158/0008-5472.CAN-12-2706