Polymorphisms in the 3'-untranslated region of the CDH1 gene are a risk factor for primary gastric diffuse large B-cell lymphoma
| Autor: | Ruta Kwiatkowski, Stephan J. Ott, Stephan Hellmig, A Titz, Wolfram Klapper, Wolfgang Fischbach, Philip Rosenstiel, Stefan Schreiber, Klaus Huse, Ulrich R. Fölsch, Gunnar Jacobs, Ralph Lucius, Andre Franke, Jochen Hampe, Markus Kosmahl |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Untranslated region Linkage disequilibrium Genotype RNA Stability Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Linkage Disequilibrium Antigens CD Risk Factors Stomach Neoplasms Gene Order medicine Humans Allele 3' Untranslated Regions Genetic Association Studies Aged Three prime untranslated region Lymphoma Non-Hodgkin Original Articles Hematology Middle Aged Cadherins medicine.disease Lymphoma Genetic Loci Mutation Allelic Imbalance Cancer research Female Lymphoma Large B-Cell Diffuse Diffuse large B-cell lymphoma |
| Zdroj: | Haematologica. 96:987-995 |
| ISSN: | 1592-8721 0390-6078 |
| Popis: | 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 (R) 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. |
| Databáze: | OpenAIRE |
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