Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer

Nat Genet. 2000 Sep;26(1):16-7. doi: 10.1038/79120.


Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers. Nonetheless, it has been challenging to demonstrate in any given tumour that methylation of a specific gene was causal and not consequent to malignant transformation. In this regard, our attention was drawn to the genesis of gastric cancers in individuals with hereditary diffuse gastric cancer (HDGC). These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1, but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. These findings suggested the hypothesis that CDH1 promoter methylation might function as the 'second genetic hit' in the genesis of these cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Cadherins / biosynthesis
  • Cadherins / genetics*
  • Cell Membrane / metabolism
  • Cytoplasm / metabolism
  • DNA Methylation*
  • Family Health
  • Female
  • Gastric Mucosa / metabolism
  • Germ-Line Mutation
  • Humans
  • Immunohistochemistry
  • Loss of Heterozygosity
  • Male
  • Microsatellite Repeats / genetics
  • Polymorphism, Genetic
  • Promoter Regions, Genetic*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism


  • Cadherins