J Med Genet 41:508-517 doi:10.1136/jmg.2004.018275
  • Original article

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

  1. A R Brooks-Wilson1,2,
  2. P Kaurah3,
  3. G Suriano4,
  4. S Leach1,
  5. J Senz5,
  6. N Grehan6,
  7. Y S N Butterfield1,
  8. J Jeyes1,
  9. J Schinas1,
  10. J Bacani7,
  11. M Kelsey3,
  12. P Ferreira4,
  13. B MacGillivray2,3,
  14. P MacLeod8,
  15. M Micek8,
  16. J Ford9,
  17. W Foulkes10,
  18. K Australie11,
  19. C Greenberg12,
  20. M LaPointe12,
  21. C Gilpin13,
  22. S Nikkel13,
  23. D Gilchrist14,
  24. R Hughes15,
  25. C E Jackson16,
  26. K G Monaghan17,
  27. M J Oliveira4,
  28. R Seruca4,
  29. S Gallinger18,
  30. C Caldas*,
  31. D Huntsman3,19,*
  1. 1Genome Sciences Centre, British Columbia Cancer Agency, 600 W. 10th Avenue, Vancouver, BC, Canada V5Z 4E6
  2. 2Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6H 3N1
  3. 3Hereditary Cancer Program, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6
  4. 4Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200 Porto, Portugal
  5. 5Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada V6H 3Z6
  6. 6Department 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. 7Samuel Lunenfeld Research Institute, University of Toronto, Toronto, ON, Canada M5G 1X5
  8. 8Medical Genetics, Victoria General Hospital, Victoria, BC, Canada V8Z 6R5
  9. 9Divisions of Oncology and Medical Genetics, Stanford University Medical Centre, Stanford, CA 94305, USA
  10. 10Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada H3G 1A4
  11. 11Division of Medical Genetics, McGill University, Montreal, QC, Canada H3G 1A4
  12. 12Section of Genetics and Metabolism, Children’s Hospital, Winnipeg, MB, Canada R3A 1R9
  13. 13Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada K1H 8L1
  14. 14Medical Genetics Clinic, University of Alberta, Edmonton, AB, Canada T6G 2R7
  15. 15Departments of Oncology and Medical Genetics, University of Calgary, Calgary, AB, Canada T2N 4N1
  16. 16Scott and White Clinic, Temple, TX 76508, USA
  17. 17Department of Medical Genetics, Henry Ford Hospital, Detroit, MI 48202, USA
  18. 18Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5
  19. 19Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada V6T 2B5
  1. Correspondence to:
 D Huntsman
 B.C. Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada V5Z 4E6;
 C Caldas
 Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Level 3, Addenbrooke’s Hospital, Cambridge CB2 2XZ, UK;
  • Accepted 19 February 2004
  • Revised 9 January 2004


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.


  • * Please note that correspondence can be addressed to both the authors indicated.

  • Conflict of interest: none declared.