Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

doi:10.1136/jmedgenet-2015-103094

Review

. 2015 Jun;52(6):361-74.

doi: 10.1136/jmedgenet-2015-103094. Epub 2015 May 15.

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

Rachel S van der Post¹, Ingrid P Vogelaar², Fátima Carneiro³, Parry Guilford⁴, David Huntsman⁵, Nicoline Hoogerbrugge², Carlos Caldas⁶, Karen E Chelcun Schreiber⁷, Richard H Hardwick⁸, Margreet G E M Ausems⁹, Linda Bardram¹⁰, Patrick R Benusiglio¹¹, Tanya M Bisseling¹², Vanessa Blair¹³, Eveline Bleiker¹⁴, Alex Boussioutas¹⁵, Annemieke Cats¹⁶, Daniel Coit¹⁷, Lynn DeGregorio¹⁸, Joana Figueiredo¹⁹, James M Ford²⁰, Esther Heijkoop²¹, Rosella Hermens²², Bostjan Humar²³, Pardeep Kaurah²⁴, Gisella Keller²⁵, Jennifer Lai⁷, Marjolijn J L Ligtenberg²⁶, Maria O'Donovan²⁷, Carla Oliveira²⁸, Hugo Pinheiro¹⁹, Krish Ragunath²⁹, Esther Rasenberg³⁰, Susan Richardson³¹, Franco Roviello³², Hans Schackert³³, Raquel Seruca²⁸, Amy Taylor³⁴, Anouk Ter Huurne³⁵, Marc Tischkowitz³⁶, Sheena Tjon A Joe²⁰, Benjamin van Dijck³⁵, Nicole C T van Grieken³⁷, Richard van Hillegersberg³⁸, Johanna W van Sandick³⁹, Rianne Vehof⁴⁰, J Han van Krieken¹, Rebecca C Fitzgerald⁴¹

Affiliations

¹ Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
² Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
³ 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.
⁴ Department of Biochemistry, University of Otago, Dunedin, New Zealand.
⁵ British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
⁶ Department of Oncology, University of Cambridge, Cambridge, UK.
⁷ No Stomach For Cancer, Inc., Madison, Wisconsin, USA.
⁸ Department of Oesophago-Gastric Surgery, Addenbrooke's Hospital, Cambridge, UK.
⁹ Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
¹⁰ Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹¹ Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
¹² Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands.
¹³ Vinery Lane Surgery, Whangarei, New Zealand.
¹⁴ Division of Psychosocial Research and Epidemiology/Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹⁵ 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.
¹⁶ Department of Gastroenterology and Hepatology, Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹⁷ Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
¹⁸ The DeGregorio Family Foundation for Stomach and Esophageal Cancer Research, Pleasantville, New York, USA.
¹⁹ 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.
²⁰ Division of Oncology, Stanford University School of Medicine, Stanford, California, USA.
²¹ Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
²² Scientific Institute for Quality of Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands.
²³ Division of Surgical Research, University of Zurich, Zurich, Suisse.
²⁴ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
²⁵ Institute of Pathology, Technische Universität, Munich, Germany.
²⁶ Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁷ Department of Histopathology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
²⁸ 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.
²⁹ NIHR Biomedical Research Unit, Nottingham Digestive Diseases Centre, Queens Medical Centre campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
³⁰ Patient representative, The Netherlands.
³¹ Department of Oncology, Familial Gastric Cancer Registry, Cambridge University Hospital, Cambridge, UK.
³² Department of General Surgery and Surgical Oncology, University of Siena, Siena, Italy.
³³ Department of Surgical Research, Technical University Dresden, Dresden, Germany.
³⁴ Cambridge University Hospital, Cambridge, UK.
³⁵ Stichting CDH1, The Netherlands.
³⁶ Department of Medical Genetics, University of Cambridge, Cambridge, UK.
³⁷ Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
³⁸ Department of Surgical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.
³⁹ Department of Surgery, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁴⁰ Radboud University Medical Center, Nijmegen, The Netherlands.
⁴¹ 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.

PMID: 25979631
PMCID: PMC4453626
DOI: 10.1136/jmedgenet-2015-103094

Review

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

Rachel S van der Post et al. J Med Genet. 2015 Jun.

. 2015 Jun;52(6):361-74.

doi: 10.1136/jmedgenet-2015-103094. Epub 2015 May 15.

Authors

Affiliations

¹ Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
² Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
³ 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.
⁴ Department of Biochemistry, University of Otago, Dunedin, New Zealand.
⁵ British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
⁶ Department of Oncology, University of Cambridge, Cambridge, UK.
⁷ No Stomach For Cancer, Inc., Madison, Wisconsin, USA.
⁸ Department of Oesophago-Gastric Surgery, Addenbrooke's Hospital, Cambridge, UK.
⁹ Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
¹⁰ Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹¹ Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
¹² Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands.
¹³ Vinery Lane Surgery, Whangarei, New Zealand.
¹⁴ Division of Psychosocial Research and Epidemiology/Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹⁵ 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.
¹⁶ Department of Gastroenterology and Hepatology, Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹⁷ Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
¹⁸ The DeGregorio Family Foundation for Stomach and Esophageal Cancer Research, Pleasantville, New York, USA.
¹⁹ 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.
²⁰ Division of Oncology, Stanford University School of Medicine, Stanford, California, USA.
²¹ Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
²² Scientific Institute for Quality of Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands.
²³ Division of Surgical Research, University of Zurich, Zurich, Suisse.
²⁴ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
²⁵ Institute of Pathology, Technische Universität, Munich, Germany.
²⁶ Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁷ Department of Histopathology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
²⁸ 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.
²⁹ NIHR Biomedical Research Unit, Nottingham Digestive Diseases Centre, Queens Medical Centre campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
³⁰ Patient representative, The Netherlands.
³¹ Department of Oncology, Familial Gastric Cancer Registry, Cambridge University Hospital, Cambridge, UK.
³² Department of General Surgery and Surgical Oncology, University of Siena, Siena, Italy.
³³ Department of Surgical Research, Technical University Dresden, Dresden, Germany.
³⁴ Cambridge University Hospital, Cambridge, UK.
³⁵ Stichting CDH1, The Netherlands.
³⁶ Department of Medical Genetics, University of Cambridge, Cambridge, UK.
³⁷ Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
³⁸ Department of Surgical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.
³⁹ Department of Surgery, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁴⁰ Radboud University Medical Center, Nijmegen, The Netherlands.
⁴¹ 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.

PMID: 25979631
PMCID: PMC4453626
DOI: 10.1136/jmedgenet-2015-103094

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.

Keywords: Cancer: breast; Cancer: gastric; Clinical genetics; Diagnostics; Stomach and duodenum.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Figures

**Figure 1.**
Algorithm for management starting from clinical hereditary diffuse gastric cancer (HDGC) testing criteria, genetic testing, role of endoscopy and gastrectomy. GC, gastric cancer; DGC, diffuse gastric cancer; LBC, lobular breast cancer; MLPA, multiplex-ligation probe amplification.

**Figure 2**
Pale areas in gastric mucosa of a patient with a germline *CDH1* mutation harbouring signet ring cell focus during white light endoscopy (A) and narrow band imaging (B). H&E stain of biopsy specimen with signet ring cells (C). Scar area after biopsy during previous endoscopy (D).

**Figure 3**
Mucosal signet ring cell carcinoma (pT1a) H&E (A), periodic acid–Schiff-diastase (B), E-cadherin (C) and cytokeratin staining (D) (original magnifications ×200).

**Figure 4**
Precursor signet ring cell lesions: pagetoid spreading of signet ring cells (A) and *in situ* signet ring cell carcinoma (B) (H&E, original magnifications ×400).

See this image and copyright information in PMC

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[1] Ferlay J. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide. IARC CancerBase 11. - PubMed

[2] Ferlay J. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide. IARC CancerBase 11. - PubMed

[3] Oliveira C, Ferreira P, Nabais S, Campos L, Ferreira A, Cirnes L, Alves CC, Veiga I, Fragoso M, Regateiro F, Dias LM, Moreira H, Suriano G, Machado JC, Lopes C, Castedo S, Carneiro F, Seruca R. E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients. Eur J Cancer 2004;40:1897–903. 10.1016/j.ejca.2004.04.027 - DOI - PubMed

[4] Oliveira C, Ferreira P, Nabais S, Campos L, Ferreira A, Cirnes L, Alves CC, Veiga I, Fragoso M, Regateiro F, Dias LM, Moreira H, Suriano G, Machado JC, Lopes C, Castedo S, Carneiro F, Seruca R. E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients. Eur J Cancer 2004;40:1897–903. 10.1016/j.ejca.2004.04.027 - DOI - PubMed

[5] Keller G, Vogelsang H, Becker I, Plaschke S, Ott K, Suriano G, Mateus AR, Seruca R, Biedermann K, Huntsman D, Doring C, Holinski-Feder E, Neutzling A, Siewert JR, Hofler H. Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients. J Med Genet 2004;41:e89 10.1136/jmg.2003.015594 - DOI - PMC - PubMed

[6] Keller G, Vogelsang H, Becker I, Plaschke S, Ott K, Suriano G, Mateus AR, Seruca R, Biedermann K, Huntsman D, Doring C, Holinski-Feder E, Neutzling A, Siewert JR, Hofler H. Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients. J Med Genet 2004;41:e89 10.1136/jmg.2003.015594 - DOI - PMC - PubMed

[7] Masciari S, Dewanwala A, Stoffel EM, Lauwers GY, Zheng H, Achatz MI, Riegert-Johnson D, Foretova L, Silva EM, Digianni L, Verselis SJ, Schneider K, Li FP, Fraumeni J, Garber JE, Syngal S. Gastric cancer in individuals with Li-Fraumeni syndrome. Genet Med 2011;13:651–7. 10.1097/GIM.0b013e31821628b6 - DOI - PMC - PubMed

[8] Masciari S, Dewanwala A, Stoffel EM, Lauwers GY, Zheng H, Achatz MI, Riegert-Johnson D, Foretova L, Silva EM, Digianni L, Verselis SJ, Schneider K, Li FP, Fraumeni J, Garber JE, Syngal S. Gastric cancer in individuals with Li-Fraumeni syndrome. Genet Med 2011;13:651–7. 10.1097/GIM.0b013e31821628b6 - DOI - PMC - PubMed

[9] Park YJ, Shin KH, Park JG. Risk of gastric cancer in hereditary nonpolyposis colorectal cancer in Korea. Clin Cancer Res 2000;6:2994–8. - PubMed

[10] Park YJ, Shin KH, Park JG. Risk of gastric cancer in hereditary nonpolyposis colorectal cancer in Korea. Clin Cancer Res 2000;6:2994–8. - PubMed

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Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

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Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

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