RESUMO
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.
Assuntos
Caderinas/genética , Metilação de DNA , Regiões Promotoras Genéticas , Neoplasias Gástricas/genética , Alelos , Caderinas/biossíntese , Membrana Celular/metabolismo , Citoplasma/metabolismo , Saúde da Família , Feminino , Mucosa Gástrica/metabolismo , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Masculino , Repetições de Microssatélites/genética , Polimorfismo Genético , Neoplasias Gástricas/metabolismoRESUMO
To extend earlier observations of germline E-cadherin mutations in kindreds with an inherited susceptibility to diffuse gastric cancer, we searched for germline E-cadherin mutations in five further families affected predominantly by diffuse gastric cancer and one family with a history of diffuse gastric cancer and early-onset breast cancer. Heterozygous inactivating mutations were found in the E-cadherin gene in each of these families. No mutation hotspots were identified. These results demonstrate that germline mutation of the E-cadherin gene is a common cause of hereditary diffuse gastric cancer and suggest a role for these mutations in the incidence of breast cancer.