title: Association of CDH1 haplotypes with susceptibility to sporadic diffuse gastric cancer.
abstract: Truncating mutations in the gene for the cell to cell adhesion protein E-cadherin are the most consistent genetic alterations observed in sporadic and hereditary diffuse gastric cancer (DGC). In addition to these inactivating mutations, a CDH1 promoter polymorphism at position -160 has been reported to lead to transcriptional downregulation of the gene in vitro. We therefore performed a case-control study to investigate whether this variant is associated with an increased susceptibility to DGC. The frequency of the -160A allele was significantly higher (P<0.005) in 53 diffuse gastric cancer cases compared to 70 matched controls. The odds ratio associated with the A-allele was 2.27 for CA-heterozygotes (95%CI 1.16-4.44) and 7.84 for AA-homozygotes (95%CI 2.89-21.24). Two additional polymorphisms (the 48+6T-->C and the 2076C-->T variant) were genotyped and shown to be equally distributed among cases and controls. Haplotype analysis with the three polymorphisms confirmed an association with disease (P<0.004). However, this analysis suggested the -160C-->A CDH1 promoter polymorphism may be in linkage disequilibrium with a distinct aetiological locus or acts in combination with other functional variants in or near the CDH1 region.
authors.affiliation: Cancer Genetics Laboratory, University of Otago, Dunedin, Aotearoa, New Zealand.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.forename: Francesco
authors.initials: F
authors.lastname: Graziano
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Catalano
authors.forename: Anna M
authors.initials: AM
authors.lastname: Ruzzo
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.forename: Tumi
authors.initials: T
authors.lastname: Toro
authors.forename: Tudor
authors.initials: T
authors.lastname: Burchill
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Futschik
authors.forename: Tony
authors.initials: T
authors.lastname: Merriman
authors.forename: Parry
authors.initials: P
authors.lastname: Guilford
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D015820:Cadherins / Q000235:genetics*; D016022:Case-Control Studies; D003062:Codon / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D007558:Italy / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D015820:Cadherins; D003062:Codon