A novel germline mutation in the MET extracellular domain in a Korean patient with the diffuse type of familial gastric cancer

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Abstract
Gastric cancer is one of the most deadly cancers world wide. Although its incidence has declined in recent years, it is still the most prevalent cancer in Asian countries such as Korea and Japan.1 Germline mutations of the cell to cell adhesion molecule E-cadherin ( CDH1 ) have been reported in patients with the diffuse type of familial gastric cancer.2,3 However, the frequency of CDH1 mutations is low overall4 and the observed mutations differ between western and Asian patients.5 Truncating mutations (that is, nonsense, frameshift, and alternative splicing mutations) predominate in patients of western origin,2,3 whereas only a few missense mutations have been found in patients of Asian extraction.5,6 This suggested that CDH1 does not play a major role in gastric cancer development in Asian countries, and prompted researchers to investigate other gastric cancer causing genes. One such gene is that for the MET receptor tyrosine kinase. MET transduces motility, proliferation, and morphogenic signals of hepatocyte growth factor/scatter factor (HGF/SF) in epithelial cells.7 Similar to other receptor tyrosine kinase genes such as RET , the MET gene encodes a protein with an extracellular domain (exon 2–13), a transmembrane domain (exon 13), and a tyrosine kinase domain (exon 15–21).8,9 MET germline mutations have been reported in patients with hereditary papillary renal carcinoma (HPRC).7 Most of the MET mutations associated with HPRC or sporadic papillary renal carcinomas7 were missense mutations in the tyrosine kinase domain,10,11 and overexpression of MET has been reported in human diseases such as breast, prostate, gastric, and ovarian cancers.12,13 In the specific context of gastric cancers, a MET germline missense mutation was found in a Korean patient suffering from intestinal gastric cancer.11 The mutation, located at the juxtamembrane domain (exon 14), …