Gastric Cancer
Copyright ©2007 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2007; 13(18): 2568-2574
Published online May 14, 2007. doi: 10.3748/wjg.v13.i18.2568
Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from Northern Brazil
Mariana Ferreira Leal, Eleonidas Moura Lima, Patrícia Natália Oliveira Silva, Paulo Pimentel Assumpção, Danielle Queiroz Calcagno, Spencer Luiz Marques Payão, Rommel Rodríguez Burbano, Marília de Arruda Cardoso Smith
Mariana Ferreira Leal, Patrícia Natália Oliveira Silva, Marília de Arruda Cardoso Smith, Genetics Division, Department of Morphology, Federal University of São Paulo, São Paulo, SP, Brazil
Eleonidas Moura Lima, Department of Biology, Campus Ministro Reis Velloso/Parnába, Federal University of Piauí, PI, Brazil
Danielle Queiroz Calcagno, Rommel Rodríguez Burbano, Human Cytogenetics and Toxicological Genetics Laboratory, Department of Biology, Center of Biological Sciences, Federal University of Pará, Belém, PA, Brazil
Paulo Pimentel Assumpção, João de Barros Barreto University Hospital, Federal University of Pará, Belém, PA, Brazil
Spencer Luiz Marques Payão, Genetics and Molecular Biology, Hemocenter, Faculty of Medicine of Marília, Marília, SP, Brazil
Author contributions: All authors contributed equally to the work.
Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior and Conselho Nacional de Desenvolvimento Científico e Tecnológico
Correspondence to: Marília de Arruda Cardoso Smith, Disciplina de Genética, Departamento de Morfologia, Universidade Federal de São Paulo/Escola Paulista de Medicina, Rua Botucatu 740, Edifício Leitão da Cunha, 1º andar, CEP: 04023-900, São Paulo, SP,Brazil. macsmith.morf@epm.br
Telephone: +55-11-55764260 Fax: +55-11-55764260
Received: January 23, 2007
Revised: January 26, 2007
Accepted: February 8, 2007
Published online: May 14, 2007
Abstract

AIM: To evaluate the methylation status of CDH1, FHIT, MTAP and PLAGL1 promoters and the association of these findings with clinico-pathological characteristics.

METHODS: Methylation-specific PCR (MSP) assay was performed in 13 nonneoplastic gastric adenocarcinoma, 30 intestinal-type gastric adenocarcinoma and 35 diffuse-type gastric adenocarcinoma samples from individuals in Northern Brazil. Statistical analyses were performed using the chi-square or Fisher's exact test to assess associations between methylation status and clinico-pathological characteristics.

RESULTS: Hypermethylation frequencies of CDH1, FHIT, MTAP and PLAGL1 promoter were 98.7%, 53.9%, 23.1% and 29.5%, respectively. Hypermethylation of three or four genes revealed a significant association with diffuse-type gastric cancer compared with nonneoplastic cancer. A higher hypermethylation frequency was significantly associated with H pylori infection in gastric cancers, especially with diffuse-type. Cancer samples without lymph node metastasis showed a higher FHIT hypermethylation frequency. MTAP hypermethylation was associated with H pylori in gastric cancer samples, as well as with diffuse-type compared with intestinal-type. In diffuse-type, MTAP hypermethylation was associated with female gender.

CONCLUSION: Our findings show differential gene methylation in tumoral tissue, which allows us to conclude that hypermethylation is associated with gastric carcinogenesis. MTAP promoter hypermethylation can be characterized as a marker of diffuse-type gastric cancer, especially in women and may help in diagnosis, prognosis and therapies. The H pylori infectious agent was present in 44.9% of the samples. This infection may be correlated with the carcinogenic process through the gene promoter hypermethylation, especially the MTAP promoter in diffuse-type. A higher H pylori infection in diffuse-type may be due to greater genetic predisposition.

Keywords: Gastric adenocarcinoma; DNA hypermethylation; CDH1; FHIT; MTAP; PLAGL1