title: Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Institute of Pathology, University of Lausanne, Lausanne, Switzerland.
authors: Pu
authors: P
authors: Yan
authors: Swiss Group for Clinical Cancer Research SAKK, Coordinating Center, Bern, Switzerland. Bioinformatics Core Facility, University of Lausanne, Lausanne, Switzerland.
authors: Dirk
authors: D
authors: Klingbiel
authors: Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Voutes, Heraklion, Greece. Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
authors: Zenia
authors: Z
authors: Saridaki
authors: Division of Anatomic Pathology, Department of Surgical and Diagnostic Sciences, University of Genoa and IRCCS S. Martino/IST University Hospital, Genoa, Italy.
authors: Paola
authors: P
authors: Ceppa
authors: Division of Anatomic Pathology, Department of Surgical and Diagnostic Sciences, University of Genoa and IRCCS S. Martino/IST University Hospital, Genoa, Italy.
authors: Monica
authors: M
authors: Curto
authors: Department of Pathology, Geneva University Hospital, Geneva, Switzerland.
authors: Thomas Alexander
authors: TA
authors: McKee
authors: Oncosurgery Unit, Geneva University Hospital, Geneva, Switzerland.
authors: Arnaud
authors: A
authors: Roth
authors: Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
authors: Sabine
authors: S
authors: Tejpar
authors: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland. Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Mauro
authors: M
authors: Delorenzi
authors: Institute of Pathology, University of Lausanne, Lausanne, Switzerland.
authors: Fredrik T
authors: FT
authors: Bosman
authors: Division of Anatomic Pathology, Department of Surgical and Diagnostic Sciences, University of Genoa and IRCCS S. Martino/IST University Hospital, Genoa, Italy. fiocca@unige.it.
authors: Roberto
authors: R
authors: Fiocca
mesh_terms: D000236:Adenoma / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000401:mortality* / Q000473:pathology*; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D053842:Microsatellite Instability; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis; D051901:Smad4 Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C497796:SMAD4 protein, human; D051901:Smad4 Protein