Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations.
Germline CDH1 mutations recently were identified in families with hereditary diffuse gastric carcinoma in a pattern suggestive of autosomal dominant inheritance with incomplete penetrance.
Our results suggest that the mRNA expression levels for pro-methylating (DNMT1, DNMT3a, DNMT3b) and anti-methylating (MBD2) enzymes is not a critical determinate of tumor-specific promoter hypermethylation of hMLH1, p(16INK4a), or CDH1 in gastric carcinoma.
No truncating or splice site CDH1 mutations were identified by PCR single-strand conformational polymorphism in these families or in eight individual patients who had both prostate and gastric cancer.
Heterozygotes with the CDH1 mutation have a 70-80% chance of developing gastric cancer and once patients have invasive, symptomatic disease there is a high associated morbidity and mortality.
These results suggest that at least two types of promoter methylation status are involved in the development of the intestinal (p16(INK4a) promoter hypermethylation) and diffuse-scattered types (CDH1 and RAR-beta promoter hypermethylation) of gastric carcinoma.
It is estimated that 25% of families meeting the criteria for hereditary diffuse gastric carcinoma (HDCG) will have germline mutations in the E-cadherin gene.
Here we report the results of germline CDH1 mutation screening in 39 kindred with familial aggregation of gastric cancer, a subset of which fulfills the criteria defined by the IGCLC for HDGC.