title: Smad4 inactivation predicts for worse prognosis and response to fluorouracil-based treatment in colorectal cancer.
abstract: OBJECTIVE
  To determine whether expression of Smad4, a tumour suppressor found to be absent in 10% of colorectal cancer (CRC), is associated with outcomes in patients with CRC.
  
  
  METHODS
  Tumour samples from 241 consecutive patients with CRC who underwent upfront colon resection between 2005 and 2009 were obtained. Triplicate tissue cores from resected primary colon tumours and matched normal controls were used to construct the tissue microarrays (TMAs). We examined the expression of Smad4 using immunohistochemistry. Clinicopathological records were obtained for all patients. TMAs were reviewed by two pathologists and scored as either 'positive' or 'negative' for nuclear staining. In total, 21 of 241 tumours (8.6%) were Smad4 negative.
  
  
  RESULTS
  Loss of Smad4 expression correlated with significantly worse overall survival (OS) (p=0.011) and disease-free survival (DFS) (p=0.024). Patients with loss of Smad4 expression had a median OS of 31 months compared with 89 months positive Smad4 expression. Loss of Smad4 remained significant on multivariate analysis for OS (p=0.0097). In patients with node-positive disease, loss of Smad4 predicts for worse DFS (p=0.012). In patients with metastatic and recurrent disease, Smad4 loss predicts for worse OS (p=0.012). Of the patients that received capecitabine over the course of their treatment, those with Smad4 loss (n=13) had significantly worse DFS (p=0.003) and OS (p=0.0007).
  
  
  CONCLUSIONS
  Loss of Smad4 expression is associated with worse DFS and OS in multiple subsets of patients with CRC. Further studies are required to validate our findings and ascertain the role of Smad4 status in the management of this disease.
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Margaret M
authors: MM
authors: Kozak
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Rie
authors: R
authors: von Eyben
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Jonathan
authors: J
authors: Pai
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Stephen R
authors: SR
authors: Vossler
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Maneesha
authors: M
authors: Limaye
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Priya
authors: P
authors: Jayachandran
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Eric M
authors: EM
authors: Anderson
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Jenny L
authors: JL
authors: Shaffer
authors: Department of Pathology, Stanford University, Stanford, California, USA.
authors: Teri
authors: T
authors: Longacre
authors: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors: Reetesh K
authors: RK
authors: Pai
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Albert C
authors: AC
authors: Koong
authors: Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.
authors: Daniel T
authors: DT
authors: Chang
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D051901:Smad4 Protein / Q000032:analysis*; D013997:Time Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000032:analysis*
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil
keywords: CANCER; CANCER RESEARCH; COLORECTAL CANCER