title: Polymorphisms in the 3'-untranslated region of the CDH1 gene are a risk factor for primary gastric diffuse large B-cell lymphoma.
abstract: BACKGROUND
  Primary gastric B-cell lymphomas arise from mucosa-associated lymphatic tissue (MALT) in patients with chronic Helicobacter pylori infection. We investigated whether germline variants in the CDH1 gene, coding for E-cadherin, genetically predispose patients to primary gastric B-cell lymphoma.
  
  
  METHODS
  Single marker analyses of the CDH1 gene were conducted in patients with primary gastric B-cell lymphoma (n=144), in patients with primary gastric high-grade lymphoma (n=61), and in healthy blood donors (n=361). Twelve single nucleotide polymorphisms were genotyped by TaqMan(®) technology. Allelic imbalance was tested by pyrosequencing and clone direct sequencing of heterozygote genomic and cDNA. Mutation detection was conducted around the poly-A signal of the CDH1 3'-untranslated region. The influence of the 3'-untranslated region on protein translation was determined by a luciferase reporter assay.
  
  
  RESULTS
  Single marker analyses identified two single nucleotide polymorphisms in strong linkage disequilibrium located in the CDH1 3'-untranslated region. One of them was significantly associated with primary gastric diffuse large B-cell lymphomas after correction for multiple testing and this association was confirmed in an independent sample set. Patients homozygous for the rare T allele (rs1801026) had a 4.9-fold increased risk (95% CI: 1.5-15.9) of developing primary gastric diffuse large B-cell lymphoma. Allelic imbalance and reporter gene assays indicated a putative influence on mRNA stability and/or translational efficacy.
  
  
  CONCLUSIONS
  We identified variants in CDH1 as the first potential genetic risk factors for the development of primary gastric diffuse large B-cell lymphomas. One of the potentially causative variants affects allelic CDH1 expression. These findings support the hypothesis that besides somatic alterations of B-cells, germline variants in the CDH1 gene contribute to a predisposition to the development of primary gastric diffuse large B-cell lymphomas.
authors: Institute of Clinical Molecular Biology, Christian-Albrechts University, Kiel, Germany.
authors: Gunnar
authors: G
authors: Jacobs
authors: Stephan
authors: S
authors: Hellmig
authors: Klaus
authors: K
authors: Huse
authors: Andrea
authors: A
authors: Titz
authors: Andre
authors: A
authors: Franke
authors: Ruta
authors: R
authors: Kwiatkowski
authors: Stephan
authors: S
authors: Ott
authors: Markus
authors: M
authors: Kosmahl
authors: Wolfgang
authors: W
authors: Fischbach
authors: Ralph
authors: R
authors: Lucius
authors: Wolfram
authors: W
authors: Klapper
authors: Ulrich R
authors: UR
authors: Fölsch
authors: Jochen
authors: J
authors: Hampe
authors: Stefan
authors: S
authors: Schreiber
authors: Philip
authors: P
authors: Rosenstiel
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D005260:Female; D023061:Gene Order; D056726:Genetic Association Studies; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020871:RNA Stability / Q000235:genetics; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins