Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk italian population

Francesco Graziano, Kazuyuki Kawakami, Annamaria Ruzzo, Go Watanabe, Daniele Santini, Francesca Pizzagalli, Renato Bisonni, Davide Mari, Irene Floriani, Vincenzo Catalano, Rosarita Silva, Giuseppe Tonini, Valter Torri, Lucio Giustini, Mauro Magnani

Research output: Contribution to journalArticle

Abstract

We performed a case-control study to examine the relationship between MTHFR C677T gene polymorphism (MTHFR677C/T) and gastric cancer susceptibility in at-risk populations in central Italy. To explore genomic DNA hypomethylation as a potential etiologic mechanism, this phenomenon was evaluated in carriers of the MTHFR677T/T genotype and carriers of the wild-type MTHFR677C/C genotype. Lymphocyte genomic DNA from 162 gastric cancer patients and 164 controls was used for MTHFR677C/T genotyping. Unconditional regression analysis with ORs and 95% CIs was used to investigate the association of the polymorphism with disease. Genomic DNA methylation status by an established enzymatic assay that measures the, DNA accepting capacity of methyl groups (inversely related to endogenous methylation) was assessed in a random sample of 40 carriers of the wild-type MTHFR677C/C genotype and 40 carriers of the MTHFR677T/T genotype. The global allelic distribution was in Hardy-Weinberg equilibrium. The MTHFR677T allele was significantly associated with gastric cancer risk with an OR of 2.49 (95% CI 1.48-4.20) in heterozygous MTHFR677C/T carriers and an OR of 2.85 (95% CI 1.52-5.35) in homozygous MTHFR677T/T carriers. This risk association was retained in subgroup analyses by tumor histotype and location. Genomic DNA hypomethylation status in MTHFR677T/T carriers was significantly higher than in subjects with wild-type MTHF677C/C genotype (p = 0.012). In the studied population, MTHFR677T played the role of a moderate-penetrance gastric cancer susceptibility allele. Possession of the MTHFR677T/T genotype was significantly associated with genomic DNA hypomethylation. These findings deserve further investigation in the context of novel strategies for gastric cancer prevention.

Original languageEnglish
Pages (from-to)628-632
Number of pages5
JournalInternational Journal of Cancer
Volume118
Issue number3
DOIs
Publication statusPublished - Mar 1 2006

Keywords

  • Cancer susceptibility
  • Gastric neoplasm
  • Methylation
  • Methylenetetrahydrofolate reductase
  • Polymorphism

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Graziano, F., Kawakami, K., Ruzzo, A., Watanabe, G., Santini, D., Pizzagalli, F., Bisonni, R., Mari, D., Floriani, I., Catalano, V., Silva, R., Tonini, G., Torri, V., Giustini, L., & Magnani, M. (2006). Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk italian population. International Journal of Cancer, 118(3), 628-632. https://doi.org/10.1002/ijc.21397