Polymorphisms in the 3′-untranslated region of the CDH1 gene are a risk factor for primary gastric diffuse large B-cell lymphoma
Polymorphisms in the 3′-untranslated region of the CDH1 gene are a risk factor for primary gastric diffuse large B-cell lymphoma
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DOI：
10.3324/haematol.2010.033126
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发表时间：
2011-07-01
期刊：
影响因子：
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通讯作者：
Rosenstiel, Philip
中科院分区：
文献类型：
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作者：
Jacobs, Gunnar;Hellmig, Stephan;Rosenstiel, Philip
原发性胃B细胞淋巴瘤起源于慢性幽门螺杆菌感染患者的粘膜相关淋巴组织(MALT)。设计与方法对144例原发性胃B细胞淋巴瘤患者、61例原发性胃高级别淋巴瘤患者和361例健康献血员进行了CDH1基因的单标记分析。采用TaqMan(R)技术对12个单核苷酸多态进行基因分型。采用焦磷酸测序和杂合子基因组克隆直接测序的方法检测等位基因的不平衡。突变检测围绕CDH13‘-非翻译区的PolyA信号进行。结果单标记分析发现CDH1 3‘非翻译区存在两个单核苷酸多态现象，存在强连锁不平衡现象。经多项检测校正后，其中一例与原发胃弥漫性大B细胞淋巴瘤显著相关，这种相关性在独立样本集中得到证实。罕见T等位基因(Rs1801026)纯合的患者发生原发胃弥漫性大B细胞淋巴瘤的风险增加4.9倍(95%可信区间：1.5-15.9)。等位基因不平衡分析和报告基因分析表明，CDH1基因变异可能影响基因的稳定性和/或翻译效率。结论CDH1基因变异是胃弥漫性大B细胞淋巴瘤发生的第一个潜在遗传危险因素。其中一个潜在的致病变异体影响等位基因CDH1的表达。这些发现支持这样的假设，即除了B细胞的躯体改变外，CDH1基因的胚系变异也是导致原发胃弥漫性大B细胞淋巴瘤的易感因素。
BackgroundPrimary 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 MethodsSingle 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.ResultsSingle 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.ConclusionsWe 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.