title: Hypermethylation of tumor-related genes in Tunisian patients with gastric carcinoma: clinical and biological significance.
abstract: BACKGROUND
  Promoter hypermethylation is an alternative mechanism of gene silencing in cancers including gastric carcinoma (GC). Its affects genes with crucial functions as tumor suppressor.
  
  
  METHODS
  DNA methylation in the promoter of P16INK4a, DAPK, retinoic acid receptor β (RARβ2), RASSF1A, and CDH1 genes was investigated in 79 Tunisian patients with GC using methylation-specific PCR.
  
  
  RESULTS
  The methylation frequencies vary from 31.6% for P16INK4a to 65.8% for RARβ2. Hypermethylation of DAPK and CDH1 was associated with tumor grade and age (P = 0.04 and 0.034) respectively, while hypermethylation of RASSF1A correlated with TNM stage (P = 0.027). The distribution of the methylated DNA at P16INK4a, DAPK, and CDH1 promoters were different in the intestinal and diffuse histotypes of GC according to TNM. Moreover, the survival rate of patients with P16INK4a methylated status was shorter than that of patients with the unmethylated status (P log rank = 0.009). On the other hand, the hypermethylation of RARβ2 correlated with COX-2 expression (P = 0.001).
  
  
  CONCLUSIONS
  We showed that methylation of P16INK4a is predictive of poor prognosis and could be a useful marker. Moreover, the association between RARβ2 methylation and COX-2 expression suggests a functional link between these two proteins in gastric carcinogenesis.
authors.affiliation: Center of Biotechnology of Sfax, Sfax, Tunisia.
authors.forename: Dorra
authors.initials: D
authors.lastname: Ben Ayed-Guerfali
authors.forename: Khemais
authors.initials: K
authors.lastname: Benhaj
authors.forename: Abdelmajid
authors.initials: A
authors.lastname: Khabir
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abid
authors.forename: Mohamed Issam
authors.initials: MI
authors.lastname: Bayrouti
authors.forename: Tahia
authors.initials: T
authors.lastname: Sellami-Boudawara
authors.forename: Ali
authors.initials: A
authors.lastname: Gargouri
authors.forename: Raja
authors.initials: R
authors.lastname: Mokdad-Gargouri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor; D015820:Cadherins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D044127:Epigenesis, Genetic; D005260:Female; D019942:Genes, p16; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015996:Survival Rate; D014416:Tunisia; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D005819:Genetic Markers; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases