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Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management

Authors' Affiliations: Departments of ¹ Pathology and Laboratory Medicine and ² Medical Genetics, University of British Columbia; ³ Hereditary Cancer Program, British Columbia Cancer Agency; and ⁴ Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada; ⁵ Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; ⁶ Division of Oncology, Departments of Medicine and Genetics, ⁷ Pathology, and ⁸ Surgery, Stanford University School of Medicine, Stanford, California; ⁹ Scott and White Clinic, Temple, Texas; ¹⁰ Departments of Surgery and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; ¹¹ Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebraska; ¹² Division of Genetics, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina; ¹³ Department of Clinical Cancer Genetics, ¹⁴ Breast Medical Oncology, M.D. Anderson Cancer Centre, Houston, Texas; ¹⁵ Front Range Cancer Specialists, Ft. Collins, Colorado; Deparments of ¹⁶ Surgery, ¹⁷ Pathology, and ¹⁸ Genetics, University of Washington, Seattle, Washington; ¹⁹ Jackson Health System University of Miami School of Medicine, Miami, Florida; ²⁰ Division of Surgical Oncology and ²¹ Department of Pathology, Emory University Medical Center, Atlanta, Georgia; ²² Department of Radiation Sciences/Oncology, Umea University, Umea, Sweden; and ²³ Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Ontario, Canada

Requests for reprints: David G. Huntsman, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. Phone: 604-877-6000; Fax: 604-872-4596; E-mail: dhuntsma{at}bccancer.bc.ca.

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.

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