title: Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Samantha
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authors.lastname: Hansford
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada5Hereditary Cancer Program, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Pardeep
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authors.lastname: Kaurah
authors.affiliation: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Hector
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authors.lastname: Li-Chang
authors.affiliation: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michelle
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authors.affiliation: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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authors.affiliation: Expression Regulation in Cancer Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
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authors.affiliation: Hereditary Cancer Program, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.lastname: Schrader
authors.affiliation: Division of Anatomical Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
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authors.lastname: Schaeffer
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Karey
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authors.lastname: Shumansky
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada9Rosalind and Morris Goodman Cancer Research Centre, Montreal, Quebec, Canada.
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authors.affiliation: Human Reproduction Service, University Hospitals of Coimbra, Coimbra, Portugal11Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Teresa Almeida
authors.initials: TA
authors.lastname: Santos
authors.affiliation: Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisbon Portugal.
authors.forename: Isabel
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authors.affiliation: Expression Regulation in Cancer Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
authors.forename: Joana
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authors.lastname: Carvalho
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada7Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Amy
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authors.affiliation: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Aline
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authors.affiliation: Frauenshuh Cancer Center, Park Nicollet Clinic, St Louis Park, Minnesota.
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authors.lastname: Baker-Lange
authors.affiliation: Cancer Research UK Cambridge Institute, Cambridge, England.
authors.forename: Sue
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authors.lastname: Richardson
authors.affiliation: Provincial Medical Genetics Program, St John's, Newfoundland, Canada.
authors.forename: Ivy
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authors.affiliation: Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona.
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authors.affiliation: Cancer Care Program, Dr. H. Bliss Murphy Cancer Centre Eastern Health, St John's, Newfoundland, Canada.
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authors.affiliation: Provincial Medical Genetics Program, St John's, Newfoundland, Canada.
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authors.affiliation: Provincial Medical Genetics Program, St John's, Newfoundland, Canada.
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authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
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authors.affiliation: Creighton's Hereditary Cancer Center, Omaha, Nebraska.
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authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Sohrab P
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authors.affiliation: Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand.
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authors.affiliation: Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada22Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto, Ontario, Canada.
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authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milano, Italy24Department of Medical Surgical Sciences and Neurosciences, Section of General Surgery and Surgical Oncology, University of Siena, Siena, Italy.
authors.forename: Giovanni
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authors.affiliation: Department of Oncology, University of Cambridge, Strangeway's Research Laboratory, Wort's Causeway, Cambridge, England28Department of Public Health and Primary Care, University of Cambridge, Strangeway's Research Laboratory, Wort's Causeway, Cambridge, En.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada7Department of Molecular.
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mesh_terms: D000328:Adult; D017677:Age Distribution; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D015820:Cadherins / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D004252:DNA Mutational Analysis; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D040941:Heredity; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D017678:Sex Distribution; D012737:Sex Factors; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins