Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management.
نویسندگان
چکیده
PURPOSE To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals. EXPERIMENTAL DESIGN We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing. RESULTS We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers. CONCLUSIONS In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.
منابع مشابه
Prophylactic gastrectomy in familial gastric cancer: case report and review of literature
Absract Gastric cancer is the fourth most common cancer and the second leading cause of cancer death. Most cases are sporadic and only 10% of patients, show familial clustering. Among these patients, 1 to 3 % have hereditary diffuse gastric cancer (HDGC), which is autosomal-dominant and present in younger ages. Mutations in Ecadherin gene CDH1 has been identified in 30 to 50% of patient...
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ورودعنوان ژورنال:
- Clinical cancer research : an official journal of the American Association for Cancer Research
دوره 11 15 شماره
صفحات -
تاریخ انتشار 2005