title: The germline CDH1 c.48 G>C substitution contributes to cancer predisposition through generation of a pro-invasive mutation.
abstract: Mutation screening of CDH1 is a standard of care for patients who meet criteria for Hereditary Diffuse Gastric Cancer (HDGC). In this setting, the classification of the sequence variants found in CDH1 is a critical step for risk management of patients with HDGC. In this report, we describe a germline CDH1 c.48 G>C variant found in a 21 year old woman and her living great uncle, who were both diagnosed with gastric cancer and belong to a family with high incidence of this type of cancer. This variant occurs at the last nucleotide of exon 1 and presumably results in a Gln-to-His change at codon 16 (Q16H). We used cloning strategies to evaluate the effects on mRNA stability and found that 5/27 and 0/17 clones have the "C" mutant allele in patient and her great uncle, respectively. In vitro functional studies revealed that the germline missense mutant (Q16H) had a pro-invasive cell behavior. Both results (functional and clinical) support the conclusion that the CDH1 c.48 G>C (Q16H) variant contributes to HDGC through the generation of a pathogenic missense mutation with loss of anti-invasive function.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: ZHANGL2@MSKCC.ORG.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Northwestern University, Evanston, IL 60208, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Xiao
authors.affiliation: Graduate School, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Ruggeri
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Bacares
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Somar
authors.affiliation: IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.
authors.forename: Soraia
authors.initials: S
authors.lastname: Melo
authors.affiliation: IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Figueiredo
authors.affiliation: IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal; Centre of Ophthalmology and Vision Sciences, IBILI - Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Simões-Correia
authors.affiliation: IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal; Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD; D016466:CHO Cells; D015820:Cadherins / Q000235:genetics*; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D018698:Glutamic Acid / Q000235:genetics; D006639:Histidine / Q000235:genetics; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D010375:Pedigree; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018698:Glutamic Acid; D006639:Histidine
keywords: CDH1; Hereditary gastric cancer; Invasion; Missense mutation