title: SMAD4 genetic alterations predict a worse prognosis in patients with pancreatic ductal adenocarcinoma.
abstract: OBJECTIVE
  The present study screened the SMAD4 gene in an Indian population of patients with pancreatic ductal adenocarcinoma (PDAC) for the presence of homozygous deletions and mutations. The effect of these genetic alterations on Smad4 protein expression and patient survival was also evaluated.
  
  
  METHODS
  This study was conducted on surgically resected paired normal and tumor tissue samples of 25 consecutive patients with PDAC. The SMAD4 gene was screened for alterations by polymerase chain reaction and polymerase chain reaction-single-strand conformation polymorphism, followed by sequencing. The log-rank test was applied for survival analysis.
  
  
  RESULTS
  The SMAD4 gene was altered in 8 (32%) of the 25 cases, 3 cases (12%) by homozygous deletion, and 5 cases (20%) by mutations in the C-terminal MH2 domain. Eighty percent of the total mutations were located in the mutational hotspot, mutation cluster region, present within the C-terminal MH2 domain. Mutations did not always result in the complete absence of protein expression. SMAD4 genetic alterations significantly correlated with poor prognosis (5 vs 10 months, log-rank test; P = 0.001).
  
  
  CONCLUSIONS
  Most SMAD4 mutations are located in the mutational hotspot, mutation cluster region, present within MH2 domain. SMAD4 mutations affect Smad4 protein expression to different extents, depending on their location within the gene. SMAD4 gene alterations predict a worse outcome for patients with PDAC.
authors.affiliation: Departments of General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India. puneetsingh_bio@y7mail.com
authors.forename: Puneet
authors.initials: P
authors.lastname: Singh
authors.forename: Radhika
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Jai Dev
authors.initials: JD
authors.lastname: Wig
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007194:India; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D016016:Proportional Hazards Models; D011446:Prospective Studies; D017422:Sequence Analysis, DNA; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; C497796:SMAD4 protein, human; D051901:Smad4 Protein