title: Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer.
abstract: Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers. Nonetheless, it has been challenging to demonstrate in any given tumour that methylation of a specific gene was causal and not consequent to malignant transformation. In this regard, our attention was drawn to the genesis of gastric cancers in individuals with hereditary diffuse gastric cancer (HDGC). These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1, but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. These findings suggested the hypothesis that CDH1 promoter methylation might function as the 'second genetic hit' in the genesis of these cancers.
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Grady
authors.forename: J
authors.initials: J
authors.lastname: Willis
authors.forename: P J
authors.initials: PJ
authors.lastname: Guilford
authors.forename: A K
authors.initials: AK
authors.lastname: Dunbier
authors.forename: T T
authors.initials: TT
authors.lastname: Toro
authors.forename: H
authors.initials: H
authors.lastname: Lynch
authors.forename: G
authors.initials: G
authors.lastname: Wiesner
authors.forename: K
authors.initials: K
authors.lastname: Ferguson
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: J G
authors.initials: JG
authors.lastname: Park
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Markowitz
mesh_terms: D000483:Alleles; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D019175:DNA Methylation; D005192:Family Health; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D015820:Cadherins