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Original Investigation
April 2015

Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond

Author Affiliations
  • 1Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
  • 2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  • 3Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
  • 4Expression Regulation in Cancer Group, IPATIMUP–Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
  • 5Hereditary Cancer Program, BC Cancer Agency, Vancouver, British Columbia, Canada
  • 6Division of Anatomical Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada
  • 7Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada
  • 8The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
  • 9Rosalind and Morris Goodman Cancer Research Centre, Montreal, Quebec, Canada
  • 10Human Reproduction Service, University Hospitals of Coimbra, Coimbra, Portugal
  • 11Faculty of Medicine, University of Coimbra, Coimbra, Portugal
  • 12Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisbon Portugal
  • 13Frauenshuh Cancer Center, Park Nicollet Clinic, St Louis Park, Minnesota
  • 14Cancer Research UK Cambridge Institute, Cambridge, England
  • 15Provincial Medical Genetics Program, St John’s, Newfoundland, Canada
  • 16Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona
  • 17Cancer Care Program, Dr. H. Bliss Murphy Cancer Centre Eastern Health, St John’s, Newfoundland, Canada
  • 18Institute of Pathology, Technische Universität München, München, Germany
  • 19Creighton’s Hereditary Cancer Center, Omaha, Nebraska
  • 20Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand
  • 21Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
  • 22Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto, Ontario, Canada
  • 23Department of Experimental Oncology, European Institute of Oncology, Milano, Italy
  • 24Department of Medical Surgical Sciences and Neurosciences, Section of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
  • 25Istituto Toscano Tumori (ITT), University Hospital of Siena, Siena, Italy
  • 26Faculty of Medicine, University of Porto, Porto, Portugal
  • 27Department of Oncology, University of Cambridge, Strangeway’s Research Laboratory, Wort’s Causeway, Cambridge, England
  • 28Department of Public Health and Primary Care, University of Cambridge, Strangeway’s Research Laboratory, Wort’s Causeway, Cambridge, England
  • 29Department of Obstetrics and Gynecology (Huntsman), University of British Columbia, Vancouver, British Columbia, Canada
JAMA Oncol. 2015;1(1):23-32. doi:10.1001/jamaoncol.2014.168
Abstract

Importance  E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options.

Objectives  To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC.

Design, Setting, and Participants  Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes.

Main Outcomes and Measures  Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers.

Results  Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation–negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2.

Conclusions and Relevance  This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

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