title: Inactivation of COX-2, HMLH1 and CDKN2A gene by promoter methylation in gastric cancer: relationship with histological subtype, tumor location and Helicobacter pylori genotype.
abstract: OBJECTIVE
  We aimed to evaluate the inactivation of COX-2, HMLH1 and CDKN2A by promoter methylation and its relationship with the infection by different Helicobacter pylori strains in gastric cancer.
  
  
  METHODS
  DNA extracted from 76 H. pylori-positive gastric tumor samples was available for promoter methylation identification by methylation-specific PCR and H. pylori subtyping by PCR. Immunohistochemistry was used to determine COX-2, p16(INK4A) and HMLH1 expression.
  
  
  RESULTS
  A strong negative correlation was found between the expression of these markers and the presence of promoter methylation in their genes. Among cardia tumors, negativity of p16(INK4A) was a significant finding. On the other hand, in noncardia tumors, the histological subtypes had different gene expression patterns. In the intestinal subtype, a significant finding was HMLH1 inactivation by methylation, while in the diffuse subtype, CDKN2A inactivation by methylation was the significant finding. Tumors with methylated COX-2 and HMLH1 genes were associated with H. pylori vacA s1 (p = 0.025 and 0.047, respectively), and the nonmethylated tumors were associated with the presence of the gene flaA.
  
  
  CONCLUSIONS
  These data suggest that the inactivation of these genes by methylation occurs by distinct pathways according to the histological subtype and tumor location and depends on the H. pylori genotype.
authors.affiliation: Genetic Section, Department of Pathology and Forensic Medicine, Federal University of Ceará, Ceará, Brazil. markenialves@yahoo.com.br
authors.forename: Markênia Kélia Santos
authors.initials: MK
authors.lastname: Alves
authors.forename: Adriana Camargo
authors.initials: AC
authors.lastname: Ferrasi
authors.forename: Valeska Portela
authors.initials: VP
authors.lastname: Lima
authors.forename: Márcia Valéria Pitombeira
authors.initials: MV
authors.lastname: Ferreira
authors.forename: Maria Inês
authors.initials: MI
authors.lastname: de Moura Campos Pardini
authors.forename: Silvia Helena Barem
authors.initials: SH
authors.lastname: Rabenhorst
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology*; D000368:Aged; D051546:Cyclooxygenase 2 / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D019942:Genes, p16; D005838:Genotype; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics / Q000382:microbiology; D016480:Helicobacter pylori / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000070957:MutL Protein Homolog 1