title: Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers.
abstract: 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.
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: van der Post
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ingrid P
authors.initials: IP
authors.lastname: Vogelaar
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal Centro Hospitalar São João, Porto, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Parry
authors.initials: P
authors.lastname: Guilford
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: No Stomach For Cancer, Inc., Madison, Wisconsin, USA.
authors.forename: Karen E Chelcun
authors.initials: KE
authors.lastname: Schreiber
authors.affiliation: Department of Oesophago-Gastric Surgery, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Hardwick
authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Margreet G E M
authors.initials: MG
authors.lastname: Ausems
authors.affiliation: Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Linda
authors.initials: L
authors.lastname: Bardram
authors.affiliation: Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Benusiglio
authors.affiliation: Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Bisseling
authors.affiliation: Vinery Lane Surgery, Whangarei, New Zealand.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Blair
authors.affiliation: Division of Psychosocial Research and Epidemiology/Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Eveline
authors.initials: E
authors.lastname: Bleiker
authors.affiliation: Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
authors.affiliation: Department of Gastroenterology and Hepatology, Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Coit
authors.affiliation: The DeGregorio Family Foundation for Stomach and Esophageal Cancer Research, Pleasantville, New York, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: DeGregorio
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Figueiredo
authors.affiliation: Division of Oncology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.affiliation: Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Heijkoop
authors.affiliation: Scientific Institute for Quality of Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rosella
authors.initials: R
authors.lastname: Hermens
authors.affiliation: Division of Surgical Research, University of Zurich, Zurich, Suisse.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Pardeep
authors.initials: P
authors.lastname: Kaurah
authors.affiliation: Institute of Pathology, Technische Universität, Munich, Germany.
authors.forename: Gisella
authors.initials: G
authors.lastname: Keller
authors.affiliation: No Stomach For Cancer, Inc., Madison, Wisconsin, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.affiliation: Department of Histopathology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: O'Donovan
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Hugo
authors.identifier: http://orcid.org/0000-0001-5329-8224
authors.initials: H
authors.lastname: Pinheiro
authors.affiliation: NIHR Biomedical Research Unit, Nottingham Digestive Diseases Centre, Queens Medical Centre campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Krish
authors.initials: K
authors.lastname: Ragunath
authors.affiliation: Patient representative, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Rasenberg
authors.affiliation: Department of Oncology, Familial Gastric Cancer Registry, Cambridge University Hospital, Cambridge, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Richardson
authors.affiliation: Department of General Surgery and Surgical Oncology, University of Siena, Siena, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Roviello
authors.affiliation: Department of Surgical Research, Technical University Dresden, Dresden, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Schackert
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.affiliation: Cambridge University Hospital, Cambridge, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Taylor
authors.affiliation: Stichting CDH1, The Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: Ter Huurne
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.affiliation: Division of Oncology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Sheena Tjon A
authors.initials: ST
authors.lastname: Joe
authors.affiliation: Stichting CDH1, The Netherlands.
authors.forename: Benjamin
authors.initials: B
authors.lastname: van Dijck
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Nicole C T
authors.initials: NC
authors.lastname: van Grieken
authors.affiliation: Department of Surgical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: van Hillegersberg
authors.affiliation: Department of Surgery, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Johanna W
authors.initials: JW
authors.lastname: van Sandick
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rianne
authors.initials: R
authors.lastname: Vehof
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: J Han
authors.initials: JH
authors.lastname: van Krieken
authors.affiliation: Cambridge NIHR Biomedical Research Centre, University of Cambridge NHS Foundation Trust MRC Cancer Unit, Hutchison/MRC Research Centre, Cambridge, UK Department Gastroenterology, Cambridge University Hospitals, UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
mesh_terms: D015703:Antigens, CD; D001943:Breast Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D015820:Cadherins / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D004252:DNA Mutational Analysis; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D005817:Genetic Counseling; D005820:Genetic Testing / Q000379:methods; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D011159:Population Surveillance; D017410:Practice Guidelines as Topic; D011247:Pregnancy; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins
keywords: Cancer: breast; Cancer: gastric; Clinical genetics; Diagnostics; Stomach and duodenum