Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer

Clin Cancer Res. 2016 Jun 15;22(12):3037-47. doi: 10.1158/1078-0432.CCR-15-0939. Epub 2016 Feb 9.


Purpose: SMAD4 loss is associated with the development of metastases and poor prognosis. We evaluated expression of SMAD4 protein and its association with tumor characteristics, including biomarkers and outcome in terms of relapse-free survival and overall survival.

Experimental design: We used 1,564 stage II/III colon cancer samples from PETACC-3 to evaluate SMAD4 expression by immunohistochemistry. SMAD4 protein expression was validated by assessing mRNA expression using available expression array data. SMAD4 expression was also studied on 34 adenomas and 10 colon cancer liver metastases with their primaries. Loss of SMAD4 immunoreactivity was defined as focal or diffuse. Cases without SMAD4 loss were subdivided into those with strong and weak expression.

Results: SMAD4 protein expression was informative in 1,381/1,564 cases. SMAD4 loss was found in 293/1,381 (21%) cases. Of 1,088 cases without SMAD4 loss (79%), 530 showed weak and 558 strong expression. SMAD4 loss occurred also in adenomas, but less extensively than in carcinomas. Liver metastases followed mostly the expression pattern of the primary tumor. SMAD4 loss, including weak expression, identified patients with poor survival in stage II as well as III and in both treatment arms. SMAD4 loss was less frequent in tumors with microsatellite instability and more frequent in those with loss of heterozygosity of 18q.

Conclusions: We conclude that clonal loss of SMAD4 expression in adenomas, carcinomas, and liver metastases increases with disease progression. SMAD4 loss, and to a lesser extent weak expression, is strongly associated with poor survival regardless of stage. Clin Cancer Res; 22(12); 3037-47. ©2016 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / pathology
  • Biomarkers, Tumor / metabolism*
  • Colonic Neoplasms / mortality*
  • Colonic Neoplasms / pathology*
  • Disease Progression
  • Disease-Free Survival
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Microsatellite Instability
  • Prognosis
  • RNA, Messenger / biosynthesis
  • Smad4 Protein / biosynthesis*
  • Smad4 Protein / genetics


  • Biomarkers, Tumor
  • RNA, Messenger
  • SMAD4 protein, human
  • Smad4 Protein