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E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma

J C Machado1, C Oliveira, R Carvalho

  • 1IPATIMUP, 4200 Porto, Portugal.

Oncogene
|April 21, 2001
PubMed

Insights

In diffuse gastric cancer, E-cadherin gene (CDH1) promoter methylation acts as the second hit, inactivating tumor suppressor genes. This finding explains CDH1 mutations without loss of heterozygosity in many gastric carcinoma cases.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Diffuse gastric carcinoma frequently exhibits E-cadherin gene (CDH1) mutations.
  • Absence of CDH1 loss of heterozygosity (LOH) in most tumors challenges the classical two-hit tumor suppressor gene inactivation model.

Purpose of the Study:

  • Investigate if CDH1 promoter methylation serves as the second hit in gastric tumorigenesis.
  • Analyze the relationship between CDH1 mutations, methylation, LOH, and E-cadherin expression.

Main Methods:

  • Analysis of 23 sporadic gastric carcinomas.
  • Detection of CDH1 mutations, CDH1 promoter methylation, LOH, and E-cadherin expression.

Main Results:

  • CDH1 mutations found in 56.3% of diffuse gastric carcinomas; none in intestinal type.
  • LOH observed in only one diffuse gastric carcinoma with CDH1 mutation.
  • CDH1 promoter methylation detected in 56.3% of diffuse gastric carcinomas, including 66.7% with CDH1 mutations.

Conclusions:

  • CDH1 promoter methylation is the second hit mechanism in over half of sporadic diffuse gastric carcinomas with CDH1 mutations.
  • This methylation explains E-cadherin loss of expression when LOH is absent.

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