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

Authors:
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
Year of publication:
2011
Volume:
96
Issue:
7
Issn:
0390-6078
Journal title abbreviated:
HAEMATOL-HEMATOL J
Journal title long:
Haematologica
Impact factor:
7.702
Abstract:
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.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.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.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.