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

Abstract

Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers1. 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 (refs 24), but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus2,3,4. These findings suggested the hypothesis that CDH1 promoter methylation might function as the ‘second genetic hit’ in the genesis of these cancers.

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Figure 1: CDH1 inactivation in HDGC tumours.
Figure 2: E-cadherin immunohistochemistry.

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Acknowledgements

We thank A. Rajput and H. Hampel. This work was supported by PHS grants KO8 CA77676 (W.M.G.), RO1 CA67409, RO1 CA72160 (S.M.), P30 CA43703, P30CA16058, CA8485 and DK20593, and by the Health Research Council of New Zealand (P.J.G.). S.M. is an associate investigator of the Howard Hughes Medical Institute.

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Correspondence to Sanford Markowitz.

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Grady, W., Willis, J., Guilford, P. et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet 26, 16–17 (2000). https://doi.org/10.1038/79120

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