A novel germ line juxtamembrane Met mutation in human gastric cancer

Activating mutations in the Met receptor tyrosine kinase, both germline and somatic, have been identified in human papillary renal cancer. Here we rep ort a novel germline missense Met mutation, P1009S, in a patient with prima ry gastric cancer. The dosage of the mutant Met DNA was elevated in the tum or when compared to its matched normal DNA. Therefore, as with hereditary r enal papillary cancer, the mutant Met allele may also be selectively duplic ated in the tumor. Different from previously reported Met mutations, which occur in the tyrosine kinase domain, this missense mutation is located at t he juxtamembrane domain, and is not constitutively activated. However, foll owing treatment with HGF/SF, the P1009S mutant Met protein, expressed in NI H3T3 cells, displays increased and persistent tyrosine phosphorylation comp ared to the wild-type Met. Importantly, these cells also form colonies in s oft agar, and are highly tumorigenic in athymic nude mice. A second nucleot ide change in this region of Met, T1010I, was found in a breast cancer biop sy and a large cell lung cancer cell line. Although this previously reporte d 'polymorphism' did not stimulate NIH3T3 cell growth in soft agar, it was more active than the wild-type Met in the athymic nude mice tumorigenesis a ssay, suggesting that it may have effects on tumorigenesis. Met has been sh own to be highly expressed in human gastric carcinoma cell lines, and our r esults raise the possibility that activating missense Met mutations could c ontribute to tumorigenesis of gastric cancer.