Hereditary diffuse gastric cancer: updated clinical practice guidelines

doi:10.1016/S1470-2045(20)30219-9

Review

. 2020 Aug;21(8):e386-e397.

doi: 10.1016/S1470-2045(20)30219-9.

Hereditary diffuse gastric cancer: updated clinical practice guidelines

Vanessa R Blair¹, Maybelle McLeod², Fátima Carneiro³, Daniel G Coit⁴, Johanna L D'Addario⁵, Jolanda M van Dieren⁶, Kirsty L Harris⁷, Nicoline Hoogerbrugge⁸, Carla Oliveira³, Rachel S van der Post⁹, Julie Arnold¹⁰, Patrick R Benusiglio¹¹, Tanya M Bisseling¹², Alex Boussioutas¹³, Annemieke Cats⁶, Amanda Charlton¹⁴, Karen E Chelcun Schreiber⁵, Jeremy L Davis¹⁵, Massimiliano di Pietro¹⁶, Rebecca C Fitzgerald¹⁶, James M Ford¹⁷, Kimberley Gamet¹⁸, Irene Gullo³, Richard H Hardwick¹⁹, David G Huntsman²⁰, Pardeep Kaurah²¹, Sonia S Kupfer²², Andrew Latchford²³, Paul F Mansfield²⁴, Takeshi Nakajima²⁵, Susan Parry¹⁰, Jeremy Rossaak²⁶, Haruhiko Sugimura²⁷, Magali Svrcek²⁸, Marc Tischkowitz²⁹, Toshikazu Ushijima³⁰, Hidetaka Yamada²⁷, Han-Kwang Yang³¹, Adrian Claydon³², Joana Figueiredo³, Karyn Paringatai³³, Raquel Seruca³, Nicola Bougen-Zhukov³⁴, Tom Brew³⁴, Simone Busija³⁵, Patricia Carneiro³, Lynn DeGregorio³⁶, Helen Fisher⁷, Erin Gardner², Tanis D Godwin³⁴, Katharine N Holm³⁷, Bostjan Humar³⁸, Caroline J Lintott³⁹, Elizabeth C Monroe³⁶, Mark D Muller⁴⁰, Enrique Norero⁴¹, Yasmin Nouri³⁴, Joana Paredes³, João M Sanches⁴², Emily Schulpen³⁴, Ana S Ribeiro³, Andrew Sporle⁴³, James Whitworth²⁹, Liying Zhang⁴⁴, Anthony E Reeve³⁴, Parry Guilford⁴⁵

Affiliations

¹ Department of Surgery, University of Auckland, Auckland, New Zealand; St Marks Breast Centre, Auckland, New Zealand.
² Kimihauora Health and Research Clinic, Mt Maunganui, New Zealand.
³ Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal.
⁴ Memorial Sloan Kettering Cancer Center and Weill Cornell Medical School, New York, NY, USA.
⁵ HereditaryDiffuseGastricCancer.org, Madison, WI, USA.
⁶ Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
⁷ Brisbane, QLD, Australia.
⁸ Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands.
⁹ Department of Pathology, Radboud University Medical Centre, Nijmegen, Netherlands.
¹⁰ New Zealand Familial Gastrointestinal Cancer Service, Auckland Hospital, Auckland, New Zealand.
¹¹ Consultation d'Oncogénétique, Unité Fonctionnelle d'Oncogénétique, Département de Génétique, DMU BioGeM, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Université, Paris, France.
¹² Department of Gastroenterology, Radboud University Medical Centre, Nijmegen, Netherlands.
¹³ Department of Medicine, Royal Melbourne Hospital and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
¹⁴ Department of Histopathology, Auckland Hospital, Auckland, New Zealand.
¹⁵ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
¹⁷ Division of Oncology, Departments of Medicine and Genetics, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ Genetic Health Service New Zealand Northern Hub, Auckland Hospital, Auckland, New Zealand.
¹⁹ Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.
²⁰ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
²¹ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Hereditary Cancer Program, British Columbia Cancer, Vancouver, BC, Canada.
²² Section of Gastroenterology, Nutrition and Hepatology, University of Chicago, Chicago, IL, USA.
²³ St Mark's Hospital, London, UK; Department of Cancer and Surgery, Imperial College, London, UK.
²⁴ University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁵ Department of Clinical Genetic Oncology, Cancer Institute Hospital, Tokyo, Japan.
²⁶ Department of Surgery, Tauranga Hospital, Tauranga, New Zealand.
²⁷ Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
²⁸ Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Department of Pathology, Hôpital Saint-Antoine, Paris, France.
²⁹ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
³⁰ Division of Epigenomics, National Cancer Centre Research Institute, Tokyo, Japan.
³¹ Seoul National University Hospital, Seoul, South Korea.
³² Department of Gastroenterology, Tauranga Hospital, Tauranga, New Zealand.
³³ Te Tumu School of Māori, Pacific and Indigenous Studies, University of Otago, Dunedin, New Zealand.
³⁴ Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand.
³⁵ No Stomach for Cancer, Madison, WI, USA.
³⁶ DeGregorio Family Foundation, New York, NY, USA.
³⁷ Department of Biochemistry and Molecular Medicine, University of California Davis School Of Medicine, Davis, CA, USA.
³⁸ Laboratory of the Swiss Hepato-Pancreato-Biliary and Transplantation Centre, Department of Surgery, University Hospital Zürich, Zurich, Switzerland.
³⁹ Genetic Health Service New Zealand South Island Hub, Christchurch Hospital, Christchurch, New Zealand.
⁴⁰ Mt Maunganui, New Zealand.
⁴¹ Esophagogastric Surgery Unit, Digestive Surgery Department, Hospital Dr Sotero del Rio, Pontificia Universidad Catolica de Chile, Santiago, Chile.
⁴² Institute for Systems and Robotics, Instituto Superior Técnico, Lisbon, Portugal.
⁴³ Healthier Lives National Science Challenge, University of Otago, Dunedin, New Zealand.
⁴⁴ Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
⁴⁵ Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand. Electronic address: parry.guilford@otago.ac.nz.

PMID: 32758476
PMCID: PMC7116190
DOI: 10.1016/S1470-2045(20)30219-9

Review

Hereditary diffuse gastric cancer: updated clinical practice guidelines

Vanessa R Blair et al. Lancet Oncol. 2020 Aug.

. 2020 Aug;21(8):e386-e397.

doi: 10.1016/S1470-2045(20)30219-9.

Authors

Affiliations

¹ Department of Surgery, University of Auckland, Auckland, New Zealand; St Marks Breast Centre, Auckland, New Zealand.
² Kimihauora Health and Research Clinic, Mt Maunganui, New Zealand.
³ Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal.
⁴ Memorial Sloan Kettering Cancer Center and Weill Cornell Medical School, New York, NY, USA.
⁵ HereditaryDiffuseGastricCancer.org, Madison, WI, USA.
⁶ Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
⁷ Brisbane, QLD, Australia.
⁸ Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands.
⁹ Department of Pathology, Radboud University Medical Centre, Nijmegen, Netherlands.
¹⁰ New Zealand Familial Gastrointestinal Cancer Service, Auckland Hospital, Auckland, New Zealand.
¹¹ Consultation d'Oncogénétique, Unité Fonctionnelle d'Oncogénétique, Département de Génétique, DMU BioGeM, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Université, Paris, France.
¹² Department of Gastroenterology, Radboud University Medical Centre, Nijmegen, Netherlands.
¹³ Department of Medicine, Royal Melbourne Hospital and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
¹⁴ Department of Histopathology, Auckland Hospital, Auckland, New Zealand.
¹⁵ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
¹⁷ Division of Oncology, Departments of Medicine and Genetics, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ Genetic Health Service New Zealand Northern Hub, Auckland Hospital, Auckland, New Zealand.
¹⁹ Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.
²⁰ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
²¹ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Hereditary Cancer Program, British Columbia Cancer, Vancouver, BC, Canada.
²² Section of Gastroenterology, Nutrition and Hepatology, University of Chicago, Chicago, IL, USA.
²³ St Mark's Hospital, London, UK; Department of Cancer and Surgery, Imperial College, London, UK.
²⁴ University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁵ Department of Clinical Genetic Oncology, Cancer Institute Hospital, Tokyo, Japan.
²⁶ Department of Surgery, Tauranga Hospital, Tauranga, New Zealand.
²⁷ Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
²⁸ Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Department of Pathology, Hôpital Saint-Antoine, Paris, France.
²⁹ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
³⁰ Division of Epigenomics, National Cancer Centre Research Institute, Tokyo, Japan.
³¹ Seoul National University Hospital, Seoul, South Korea.
³² Department of Gastroenterology, Tauranga Hospital, Tauranga, New Zealand.
³³ Te Tumu School of Māori, Pacific and Indigenous Studies, University of Otago, Dunedin, New Zealand.
³⁴ Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand.
³⁵ No Stomach for Cancer, Madison, WI, USA.
³⁶ DeGregorio Family Foundation, New York, NY, USA.
³⁷ Department of Biochemistry and Molecular Medicine, University of California Davis School Of Medicine, Davis, CA, USA.
³⁸ Laboratory of the Swiss Hepato-Pancreato-Biliary and Transplantation Centre, Department of Surgery, University Hospital Zürich, Zurich, Switzerland.
³⁹ Genetic Health Service New Zealand South Island Hub, Christchurch Hospital, Christchurch, New Zealand.
⁴⁰ Mt Maunganui, New Zealand.
⁴¹ Esophagogastric Surgery Unit, Digestive Surgery Department, Hospital Dr Sotero del Rio, Pontificia Universidad Catolica de Chile, Santiago, Chile.
⁴² Institute for Systems and Robotics, Instituto Superior Técnico, Lisbon, Portugal.
⁴³ Healthier Lives National Science Challenge, University of Otago, Dunedin, New Zealand.
⁴⁴ Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
⁴⁵ Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand. Electronic address: parry.guilford@otago.ac.nz.

PMID: 32758476
PMCID: PMC7116190
DOI: 10.1016/S1470-2045(20)30219-9

Abstract

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

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Conflict of interest statement

Conflicts of interest

PRB reports personal fees from AstraZeneca, Janssen and Roche Diagnostics and non-financial support from GENETICANCER, outside the submitted work. DGH is founder and CMO of Contextual Genomics. The work of Contextual Genomics in no way overlaps with the topics of this review. LZ received other support from Future Technology Research LLC, Roche Diagnostics Asia Pacific, BGI, and Illumina, outside the submitted work. A family member of LZ has a leadership position and ownership interest in the Shanghai Genome Center. All other authors declare no competing interests.

Figures

**Fig. 1**
Flow chart for the management of individuals and families who either meet the revised HDGC genetic testing criteria or have had a pathogenic *CDH1* variant identified through another route.

**Fig. 2. Endoscopic and histopathological images of HDGC gastric lesions. A-B**
**A-B:** Superficial pT1a SRCC focus. A) Endoscopy of non-elevated pale lesion. B) Corresponding histology showing SRCs with “indolent” phenotype superficially in the *lamina propria*. **C-D:** Intramucosal pT1a SRCC focus with invasion into the deeper *lamina propria*. C) Endoscopy of 1mm erosive lesion in middle of coarse pit pattern. D) Corresponding histology showing deeper invasion of SRCs almost reaching the *muscularis musosae* (asterisk). **E-F:** Precursor gastric lesions in hereditary diffuse gastric cancer (HDGC) E) *In situ* SRC carcinoma (dotted line) displaying SRCs within basal membrane. F) Pagetoid spread of SRCs (arrows) below the preserved epithelium. **G-H:** Invasive HDGC gastric lesions within the *lamina propria*. G) Intramucosal SRCC focus (H&E) and H) PAS-D staining. **I-J:** Intratumoral heterogeneity displayed in two biopsies from the same tumour. I) DGC with typical SRCs (indolent phenotype). J) DGC with pleomorphic, bizarre cells (aggressive phenotype). **K-L:** Advanced DGC. K) Invasion of gastric wall with prominent desmoplastic response. L) Peritoneal metastasis.

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References

1. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402–05. - PubMed
1. Hansford S, Kaurah P, Li-Chang H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncology. 2015;1:23–32. - PubMed
1. Lecuit T, Yap AS. E-cadherin junctions as active mechanical integrators in tissue dynamics. Nat Cell Biol. 2015;17:533–9. - PubMed
1. Majewski IJ, Kluijt I, Cats A, et al. An alpha-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol. 2013;229:621–9. - PubMed
1. Lowstuter K, Espendchied CR, Sturgeon D, et al. Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges. JCO Precision Oncology. 2017;1:1–12. - PubMed

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[1] Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402–05. - PubMed

[2] Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402–05. - PubMed

[3] Hansford S, Kaurah P, Li-Chang H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncology. 2015;1:23–32. - PubMed

[4] Hansford S, Kaurah P, Li-Chang H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncology. 2015;1:23–32. - PubMed

[5] Lecuit T, Yap AS. E-cadherin junctions as active mechanical integrators in tissue dynamics. Nat Cell Biol. 2015;17:533–9. - PubMed

[6] Lecuit T, Yap AS. E-cadherin junctions as active mechanical integrators in tissue dynamics. Nat Cell Biol. 2015;17:533–9. - PubMed

[7] Majewski IJ, Kluijt I, Cats A, et al. An alpha-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol. 2013;229:621–9. - PubMed

[8] Majewski IJ, Kluijt I, Cats A, et al. An alpha-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol. 2013;229:621–9. - PubMed

[9] Lowstuter K, Espendchied CR, Sturgeon D, et al. Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges. JCO Precision Oncology. 2017;1:1–12. - PubMed

[10] Lowstuter K, Espendchied CR, Sturgeon D, et al. Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges. JCO Precision Oncology. 2017;1:1–12. - PubMed

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Hereditary diffuse gastric cancer: updated clinical practice guidelines

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Hereditary diffuse gastric cancer: updated clinical practice guidelines

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