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Published on: February 5, 2018
Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer
W M Grady1, J Willis, P J Guilford
1Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, USA.
Abstract:
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.
Insights
Aberrant promoter methylation is linked to human cancers. In hereditary diffuse gastric cancer, CDH1 promoter methylation may act as the crucial second genetic hit, driving cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Aberrant promoter methylation and gene silencing are hallmarks of human cancers.
- Demonstrating causality between specific gene methylation and tumorigenesis remains challenging.
- Hereditary diffuse gastric cancer (HDGC) provides a unique model due to germline CDH1 mutations.
Purpose of the Study:
- To investigate the role of E-cadherin (CDH1) promoter methylation in the genesis of gastric cancers within HDGC patients.
- To test the hypothesis that CDH1 promoter methylation acts as a critical 'second genetic hit' in HDGC tumorigenesis.
Main Methods:
- Analysis of CDH1 promoter methylation status in gastric tumors from HDGC individuals.
- Correlation of methylation data with gene expression and loss of heterozygosity at the CDH1 locus.
Main Results:
- Gastric cancers in HDGC patients consistently show absence of loss of heterozygosity at the CDH1 locus.
- This suggests an alternative mechanism for biallelic inactivation of CDH1.
Conclusions:
- CDH1 promoter methylation is a likely causal event in gastric cancer development in HDGC patients.
- This epigenetic event functions as the 'second hit' complementing the inherited CDH1 mutation, driving tumorigenesis.
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