title: Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1.
abstract: OBJECTIVE
  Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50.
  
  
  METHODS
  We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations.
  
  
  RESULTS
  In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years (P = .014 for comparative survival analysis between patients with and without a CDH1 mutation).
  
  
  CONCLUSIONS
  All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.
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: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Peggy
authors.initials: P
authors.lastname: Manders
authors.affiliation: Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Lizet E
authors.initials: LE
authors.lastname: van der Kolk
authors.affiliation: Department of Gastroenterology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Liselotte P
authors.initials: LP
authors.lastname: van Hest
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Rolf
authors.initials: R
authors.lastname: Sijmons
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cora M
authors.initials: CM
authors.lastname: Aalfs
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Margreet G E M
authors.initials: MG
authors.lastname: Ausems
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Encarna B
authors.initials: EB
authors.lastname: Gómez García
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Neeltje
authors.initials: N
authors.lastname: Arts
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Arjen R
authors.initials: AR
authors.lastname: Mensenkamp
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: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Marjolijn.Ligtenberg@radboudumc.nl.
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015820:Cadherins / Q000235:genetics*; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D040941:Heredity; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D009426:Netherlands; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015996:Survival Rate; D013997:Time Factors; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins
keywords: Carcinogenesis; Genetic Risk Factor; LBC; Stomach