SMAD4 genetic alterations predict a worse prognosis in patients with pancreatic ductal adenocarcinoma.

Objectives: 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.