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Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria

¹ Genome Sciences Centre, British Columbia Cancer Agency, 600 W. 10th Avenue, Vancouver, BC, Canada V5Z 4E6
² Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6H 3N1
³ Hereditary Cancer Program, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6
⁴ Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200 Porto, Portugal
⁵ Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada V6H 3Z6
⁶ Department of Oncology, University of Cambridge and Wellcome Trust Centre for Molecular Mechanisms in Disease/Cambridge Institute for Medical Research, Wellcome Trust/MRC Building Level 6, Cambridge CB2 2XY, UK
⁷ Samuel Lunenfeld Research Institute, University of Toronto, Toronto, ON, Canada M5G 1X5
⁸ Medical Genetics, Victoria General Hospital, Victoria, BC, Canada V8Z 6R5
⁹ Divisions of Oncology and Medical Genetics, Stanford University Medical Centre, Stanford, CA 94305, USA
¹⁰ Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada H3G 1A4
¹¹ Division of Medical Genetics, McGill University, Montreal, QC, Canada H3G 1A4
¹² Section of Genetics and Metabolism, Children’s Hospital, Winnipeg, MB, Canada R3A 1R9
¹³ Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada K1H 8L1
¹⁴ Medical Genetics Clinic, University of Alberta, Edmonton, AB, Canada T6G 2R7
¹⁵ Departments of Oncology and Medical Genetics, University of Calgary, Calgary, AB, Canada T2N 4N1
¹⁶ Scott and White Clinic, Temple, TX 76508, USA
¹⁷ Department of Medical Genetics, Henry Ford Hospital, Detroit, MI 48202, USA
¹⁸ Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5
¹⁹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada V6T 2B5

Correspondence to:
D Huntsman
B.C. Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada V5Z 4E6; dhuntsma{at}bccancer.bc.ca
C Caldas
Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Level 3, Addenbrooke’s Hospital, Cambridge CB2 2XZ, UK; cc234{at}cam.ac.uk] Background: Mutations in the E-cadherin (CDH1) gene are a well documented cause of hereditary diffuse gastric cancer (HDGC). Development of evidence based guidelines for CDH1 screening for HDGC have been complicated by its rarity, variable penetrance, and lack of founder mutations.

Methods: Forty three new gastric cancer (GC) families were ascertained from multiple sources. In 42 of these families at least one gastric cancer was pathologically confirmed to be a diffuse gastric cancer (DGC); the other family had intestinal type gastric cancers. Screening of the entire coding region of the CDH1 gene and all intron/exon boundaries was performed by bi-directional sequencing.

Results: Novel mutations were found in 13 of the 42 DGC families (31% overall). Twelve of these mutations occur among the 25 families with multiple cases of gastric cancer and with pathologic confirmation of diffuse gastric cancer phenotype in at least one individual under the age of 50 years. The mutations found include small insertions and deletions, splice site mutations, and three non-conservative amino acid substitutions (A298T, W409R, and R732Q). All three missense mutations conferred loss of E-cadherin function in in vitro assays. Multiple cases of breast cancers including pathologically confirmed lobular breast cancers were observed both in mutation positive and negative families.

Conclusion: Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age. We recommend that these criteria be used for selecting families for CDH1 mutational analysis.

Abbreviations: FAP, familial adenomatous polyposis; FFPE, formalin-fixed paraffin embedded; HDGC, hereditary diffuse gastric cancer; HNPCC, hereditary non-polyposis colon cancer; IGC, intestinal type gastric cancer; LCIS, lobular breast carcinoma in situ; PJS, Peutz-Jeghers syndrome

Keywords: CDH1; E-cadherin; gastric cancer; hereditary diffuse gastric cancer; mutation

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