Hereditary diffuse gastric cancer (MIM#137215) is an autosomal dominant disease in which gastric cancer develops at a young age. The first report in the medical literature describing familial clustering of gastric cancer was that of Aldred Warthin in 1913, although this family (“family G”) was subsequently shown to have hereditary non-polyposis colorectal cancer (HNPCC).^1–3 Further reports of familial predisposition to gastric cancer were, likewise, indirect and based only on clinical and epidemiological observation. Direct proof of a clear molecular basis for diffuse gastric cancer was identified only 6 years ago, when Parry Guilford and colleagues demonstrated germline inactivating mutation of the CDH1 (E-cadherin) gene in a large New Zealand family of Maori ethnicity with early onset, diffuse gastric cancer.⁴ Shortly thereafter, it was shown that CDH1 inactivating mutation accounted for a proportion of European families with gastric cancer, a few families of Japanese and Korean ethnicity, as well as one family each of African-American and Pakistani origin.^4–12 Importantly, all these families have diffuse-type gastric cancer. This specificity of tumour type and association with CDH1 germline mutation led to the designation of hereditary diffuse gastric cancer (HDGC) by the International Gastric Cancer Linkage Consortium (IGCLC).¹³ Preliminary analysis of these families has suggested that penetrance for gastric cancer is upwards to 70%. A few studies also suggest an increased risk for colon cancer and lobular breast cancer although this remains open for debate.^6,10,14

The full-length human CDH1 was cloned and isolated from its location on chromosome 16q22.1 in 1995.¹⁵ It has 16 exons spanning approximately 100 kb of genomic DNA. The gene structure is similar to that of other cadherins. The mature E-cadherin protein consists of three major domains: a large extracellular portion (exons …