title: Epigenetic Silencing of GNMT Gene in Pancreatic Adenocarcinoma.
abstract: OBJECTIVE
  Although pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for therapy, biomarkers for early detection are lacking. Epigenetic silencing of tumor suppressor genes is a majorcontributor to neoplastic transformation. The aim of this study was to identify new factors involved in PDAC progression. The GNMT gene possesses CpG islands in the promoter region and is important in methyl-group metabolism and in maintaining a normal methylation status of the genome.
  
  
  METHODS
  To test the hypothesis whether GNMT is epigenetically regulated in PDAC, we evaluated the GNMT gene expression and promoter methylation status in 30 paired samples of PDAC and normal pancreatic tissue.
  
  
  RESULTS
  We found significantly higher methylation frequencies (p<0.001) in PDACs (2.82-100%; median, 36.05%) than in controls (0.28-14.02%; median, 4.39%). The GNMT gene expression was decreased in PDACs compared to normal pancreatic tissues in 26/30 cases (86.67%). Furthermore, we showed that treatment with 5-aza-2-deoxycytidine (5-aza-dC) increased GNMT mRNA expression and decreased viability in PDAC cells.
  
  
  CONCLUSIONS
  Collectively, these data indicate that GNMT is aberrantly methylated in PDAC representing, thus, a potential major mechanism for gene silencing. Methylation of GNMT gene is directly correlated with disease stage and with tumor grade indicating that these epigenetic effects may be important regulators of PDAC progression.
authors.affiliation: Viral Genetic Engineering Laboratory, Romanian Academy "Stefan S. Nicolau"Virology Institute, Bucharest, Romania.
authors.forename: Anca
authors.initials: A
authors.lastname: Botezatu
authors.affiliation: Antiviral Therapy Engineering Laboratory, Romanian Academy "Stefan S. Nicolau" Virology Institute, Bucharest, Romania.
authors.forename: Coralia
authors.initials: C
authors.lastname: Bleotu
authors.affiliation: Center of General Surgery and Liver Transplantation "Dan Setlacec", Fundeni Clinical Institute, Bucharest, Romania.
authors.forename: Anca
authors.initials: A
authors.lastname: Nastase
authors.affiliation: Viral Genetic Engineering Laboratory, Romanian Academy "Stefan S. Nicolau"Virology Institute, Bucharest, Romania.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Anton
authors.affiliation: "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.
authors.forename: Nicolae
authors.initials: N
authors.lastname: Bacalbasa
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Charlestown, MA, U.S.A.
authors.forename: Dan
authors.initials: D
authors.lastname: Duda
authors.affiliation: Center of General Surgery and Liver Transplantation "Dan Setlacec", Fundeni Clinical Institute, Bucharest, Romania.
authors.forename: Simona Olimpia
authors.initials: SO
authors.lastname: Dima
authors.affiliation: Center of General Surgery and Liver Transplantation "Dan Setlacec", Fundeni Clinical Institute, Bucharest, Romania.
authors.forename: Irinel
authors.initials: I
authors.lastname: Popescu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008875:Middle Aged; D011379:Prognosis
keywords: Epigenetic alteration; pancreatic cancer; promoter methylation