title: Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management.
abstract: OBJECTIVE
  To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals.
  
  
  METHODS
  We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing.
  
  
  RESULTS
  We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers.
  
  
  CONCLUSIONS
  In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Suriano
authors.forename: Sandie
authors.initials: S
authors.lastname: Yew
authors.forename: Paulo
authors.initials: P
authors.lastname: Ferreira
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.forename: Pardeep
authors.initials: P
authors.lastname: Kaurah
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.forename: Teri A
authors.initials: TA
authors.lastname: Longacre
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Norton
authors.forename: Nicki
authors.initials: N
authors.lastname: Chun
authors.forename: Sean
authors.initials: S
authors.lastname: Young
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Oliveira
authors.forename: Barbara
authors.initials: B
authors.lastname: Macgillivray
authors.forename: Arundhati
authors.initials: A
authors.lastname: Rao
authors.forename: Dawn
authors.initials: D
authors.lastname: Sears
authors.forename: Charles E
authors.initials: CE
authors.lastname: Jackson
authors.forename: Jeff
authors.initials: J
authors.lastname: Boyd
authors.forename: Cindy
authors.initials: C
authors.lastname: Yee
authors.forename: Carolyn
authors.initials: C
authors.lastname: Deters
authors.forename: G Shashidhar
authors.initials: GS
authors.lastname: Pai
authors.forename: Lyn S
authors.initials: LS
authors.lastname: Hammond
authors.forename: Bobbi J
authors.initials: BJ
authors.lastname: McGivern
authors.forename: Diane
authors.initials: D
authors.lastname: Medgyesy
authors.forename: Denise
authors.initials: D
authors.lastname: Sartz
authors.forename: Banu
authors.initials: B
authors.lastname: Arun
authors.forename: Brant K
authors.initials: BK
authors.lastname: Oelschlager
authors.forename: Mellisa P
authors.initials: MP
authors.lastname: Upton
authors.forename: Whitney
authors.initials: W
authors.lastname: Neufeld-Kaiser
authors.forename: Orlando E
authors.initials: OE
authors.lastname: Silva
authors.forename: Talia R
authors.initials: TR
authors.lastname: Donenberg
authors.forename: David A
authors.initials: DA
authors.lastname: Kooby
authors.forename: Shobha
authors.initials: S
authors.lastname: Sharma
authors.forename: Björn-Anders
authors.initials: BA
authors.lastname: Jonsson
authors.forename: Henrik
authors.initials: H
authors.lastname: Gronberg
authors.forename: Steve
authors.initials: S
authors.lastname: Gallinger
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Henry
authors.initials: H
authors.lastname: Lynch
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D018389:Codon, Nonsense; D003094:Collagen / Q000494:pharmacology; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000378:metabolism; D004338:Drug Combinations; D005091:Exons; D018095:Germ-Line Mutation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008875:Middle Aged; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness; D010375:Pedigree; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000494:pharmacology; D012306:Risk; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000235:genetics*
chemical_list: D015820:Cadherins; D018389:Codon, Nonsense; D017931:DNA Primers; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen