CDKN2A promoter methylation is related to the tumor location and histological subtype and associated with Helicobacter pylori flaA(+) strains in gastric adenocarcinomas.
Promoter hypermethylation of CDKN2A (p16INK4A protein) is the main mechanism of gene inactivation. However, its association with Helicobacter pylori infection is a controversial issue. Therefore, we examined a series of gastric adenocarcinomas to assess the association between p16INK4A inactivation and H. pylori genotype (vacA, cagA, cagE, virB11 and flaA) according to the location and histological subtype of the tumors. p16INK4A expression and CDKN2A promoter methylation were found in 77 gastric adenocarcinoma samples by immunohistochemistry and methylation-specific PCR, respectively. Helicobacter pylori infection and genotype were determined by PCR. A strong negative correlation between immunostaining and CDKN2A promoter region methylation was found. In diffuse subtype tumors, the inactivation of p16INK4A by promoter methylation was unique in noncardia tumors (p=0.022). In addition, H. pylori-bearing flaA was associated with non-methylation tumors (p=0.008) and H. pylori strain bearing cagA or vacAs1m1 genes but without flaA was associated with methylated tumors (p=0.022 and 0.003, respectively). Inactivation of p16INK4A in intestinal and diffuse subtypes showed distinct carcinogenic pathways, depending on the tumor location. Moreover, the process of methylation of the CDKN2A promoter seems to depend on the H. pylori genotype. The present data suggest that there is a differential influence and relevance of H. pylori genotype in gastric cancer development.
Alves
Markênia Kélia Santos
MK
Microbiology Section, Department of Pathology and Forensic Medicine, Federal University of Ceará, Porangabussu Campus, Ceará, Brazil. markenialves@yahoo.com.br
Lima
Valeska Portela
VP
Ferrasi
Adriana Camargo
AC
Rodrigues
Maria Aparecida
MA
De Moura Campos Pardini
Maria Inês
MI
Rabenhorst
Silvia Helena Barem
SH
D000230:Adenocarcinoma / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D019942:Genes, p16; D016481:Helicobacter Infections / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology / Q000473:pathology
D019941:Cyclin-Dependent Kinase Inhibitor p16