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Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers
  1. Rachel S van der Post1,
  2. Ingrid P Vogelaar2,
  3. Fátima Carneiro3,4,5,6,
  4. Parry Guilford7,
  5. David Huntsman8,
  6. Nicoline Hoogerbrugge2,
  7. Carlos Caldas9,
  8. Karen E Chelcun Schreiber10,
  9. Richard H Hardwick11,
  10. Margreet G E M Ausems12,
  11. Linda Bardram13,
  12. Patrick R Benusiglio14,
  13. Tanya M Bisseling15,
  14. Vanessa Blair16,
  15. Eveline Bleiker17,
  16. Alex Boussioutas18,19,
  17. Annemieke Cats20,
  18. Daniel Coit21,
  19. Lynn DeGregorio22,
  20. Joana Figueiredo3,4,
  21. James M Ford23,
  22. Esther Heijkoop24,
  23. Rosella Hermens25,
  24. Bostjan Humar26,
  25. Pardeep Kaurah27,
  26. Gisella Keller28,
  27. Jennifer Lai10,
  28. Marjolijn J L Ligtenberg1,2,
  29. Maria O'Donovan29,
  30. Carla Oliveira3,4,5,
  31. Hugo Pinheiro3,4,
  32. Krish Ragunath30,
  33. Esther Rasenberg31,
  34. Susan Richardson32,
  35. Franco Roviello33,
  36. Hans Schackert34,
  37. Raquel Seruca3,4,5,
  38. Amy Taylor35,
  39. Anouk ter Huurne36,
  40. Marc Tischkowitz37,
  41. Sheena Tjon A Joe23,
  42. Benjamin van Dijck36,
  43. Nicole C T van Grieken38,
  44. Richard van Hillegersberg39,
  45. Johanna W van Sandick40,
  46. Rianne Vehof41,
  47. J Han van Krieken1,
  48. Rebecca C Fitzgerald42,43,44
  1. 1Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  3. 3Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
  4. 4Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
  5. 5Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal
  6. 6Centro Hospitalar São João, Porto, Portugal
  7. 7Department of Biochemistry, University of Otago, Dunedin, New Zealand
  8. 8British Columbia Cancer Agency, Vancouver, British Columbia, Canada
  9. 9Department of Oncology, University of Cambridge, Cambridge, UK
  10. 10No Stomach For Cancer, Inc., Madison, Wisconsin, USA
  11. 11Department of Oesophago-Gastric Surgery, Addenbrooke's Hospital, Cambridge, UK
  12. 12Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  13. 13Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  14. 14Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France
  15. 15Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands
  16. 16Vinery Lane Surgery, Whangarei, New Zealand
  17. 17Division of Psychosocial Research and Epidemiology/Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  18. 18Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  19. 19Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
  20. 20Department of Gastroenterology and Hepatology, Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  21. 21Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  22. 22The DeGregorio Family Foundation for Stomach and Esophageal Cancer Research, Pleasantville, New York, USA
  23. 23Division of Oncology, Stanford University School of Medicine, Stanford, California, USA
  24. 24Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  25. 25Scientific Institute for Quality of Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands
  26. 26Division of Surgical Research, University of Zurich, Zurich, Suisse
  27. 27Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
  28. 28Institute of Pathology, Technische Universität, Munich, Germany
  29. 29Department of Histopathology, Cambridge University Hospitals NHS Trust, Cambridge, UK
  30. 30NIHR Biomedical Research Unit, Nottingham Digestive Diseases Centre, Queens Medical Centre campus, Nottingham University Hospitals NHS Trust, Nottingham, UK
  31. 31Patient representative, The Netherlands
  32. 32Department of Oncology, Familial Gastric Cancer Registry, Cambridge University Hospital, Cambridge, UK
  33. 33Department of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
  34. 34Department of Surgical Research, Technical University Dresden, Dresden, Germany
  35. 35Cambridge University Hospital, Cambridge, UK
  36. 36Stichting CDH1, The Netherlands
  37. 37Department of Medical Genetics, University of Cambridge, Cambridge, UK
  38. 38Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
  39. 39Department of Surgical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands
  40. 40Department of Surgery, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  41. 41Radboud University Medical Center, Nijmegen, The Netherlands
  42. 42Cambridge NIHR Biomedical Research Centre, University of Cambridge NHS Foundation Trust
  43. 43MRC Cancer Unit, Hutchison/MRC Research Centre, Cambridge, UK
  44. 44Department Gastroenterology, Cambridge University Hospitals, UK
  1. Correspondence to Professor Rebecca C Fitzgerald, MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 OXZ, UK; rcf29{at}


Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

  • Cancer: gastric
  • Clinical genetics
  • Diagnostics
  • Cancer: breast
  • Stomach and duodenum

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