Haematologica (Jul 2011)

Polymorphisms in the 3′-untranslated region of the CDH1 gene are a risk factor for primary gastric diffuse large B-cell lymphoma

  • Gunnar Jacobs,
  • Stephan Hellmig,
  • Klaus Huse,
  • Andrea Titz,
  • Andre Franke,
  • Ruta Kwiatkowski,
  • Stephan Ott,
  • Markus Kosmahl,
  • Wolfgang Fischbach,
  • Ralph Lucius,
  • Wolfram Klapper,
  • Ulrich R. Fölsch,
  • Jochen Hampe,
  • Stefan Schreiber,
  • Philip Rosenstiel

DOI
https://doi.org/10.3324/haematol.2010.033126
Journal volume & issue
Vol. 96, no. 7

Abstract

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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.Design and 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.