DNA甲基化分析确定E-钙黏蛋白基因是单克隆丙种球蛋白病患者疾病进展的潜在标志物。
DNA-methylation analysis identifies the E-cadherin gene as a potential marker of disease progression in patients with monoclonal gammopathies.
作者信息
Seidl Sonja, Ackermann Jutta, Kaufmann Hannes, Keck Andrea, Nösslinger Thomas, Zielinski Christoph C, Drach Johannes, Zöchbauer-Müller Sabine
机构信息
Clinical Division of Oncology, Department of Medicine I, University Hospital, Vienna, Austria.
出版信息
Cancer. 2004 Jun 15;100(12):2598-606. doi: 10.1002/cncr.20295.
BACKGROUND
Silencing of tumor suppressor genes (TSG) by aberrant methylation (referred to as methylation) contributes to the pathogenesis of various human malignancies. However, little is known about the methylation of known and putative TSGs in monoclonal gammopathies. Thus, the authors investigated the methylation frequencies of 10 genes in patients with monoclonal gammopathies.
METHODS
The methylation patterns of the genes p16(INK4a) (p16), tissue inhibitor of metalloproteinase 3 (TIMP3), p15(INK4b) (p15), E-cadherin (ECAD), death-associated protein kinase (DAPK), p73, RAS-association domain family 1A (RASSF1A), p14, O(6)-methylguanine DNA methyltransferase (MGMT), and retinoid acid receptor beta2 (RARbeta) were determined in patients with monoclonal gammopathy of undetermined significance (MGUS; n = 29), smoldering multiple myeloma (SMM; n = 5), multiple myeloma (MM; n = 113), or plasma cell leukemia (PCL; n = 7) by methylation-specific polymerase chain reaction analysis.
RESULTS
Methylation frequencies for p16, TIMP3, p15, ECAD, DAPK, p73, RASSF1A, p14, MGMT, and RARbeta were as follows: 28%, 35%, 10%, 0%, 17%, 21%, 14%, 14%, 7%, and 0%, respectively, in patients with MGUS and 36%, 29%, 27%, 27%, 22%, 15%, 15%, 9%, 4%, and 0%, respectively, in patients with MM. Methylation of at least 1 of these genes was detected in 79% of patients with MGUS and in 80% of patients with MM. Although methylation of ECAD was not detected in patients with MGUS, it was observed frequently in patients with MM and with even greater frequency in patients with PCL. It is noteworthy that an association was found between ECAD methylation and poor prognostic markers in patients with MM.
CONCLUSIONS
Methylation of certain genes can be detected frequently in patients with monoclonal gammopathies. The current data suggest that methylation of ECAD is a marker of disease progression in patients with MM and PCL.
背景
肿瘤抑制基因（TSG）因异常甲基化（称为甲基化）而沉默，这在多种人类恶性肿瘤的发病机制中起作用。然而，对于单克隆丙种球蛋白病中已知和假定的TSG的甲基化情况知之甚少。因此，作者调查了单克隆丙种球蛋白病患者中10个基因的甲基化频率。
方法
采用甲基化特异性聚合酶链反应分析，测定意义未明的单克隆丙种球蛋白病（MGUS；n = 29）、冒烟型多发性骨髓瘤（SMM；n = 5）、多发性骨髓瘤（MM；n = 113）或浆细胞白血病（PCL；n = 7）患者中p16（INK4a）（p16）、金属蛋白酶组织抑制剂3（TIMP3）、p15（INK4b）（p15）、E-钙黏蛋白（ECAD）、死亡相关蛋白激酶（DAPK）、p73、RAS关联结构域家族1A（RASSF1A）、p14、O（6）-甲基鸟嘌呤-DNA甲基转移酶（MGMT）和视黄酸受体β2（RARβ）基因的甲基化模式。
结果
MGUS患者中p16、TIMP3、p15、ECAD、DAPK、p73、RASSF1A、p14、MGMT和RARβ的甲基化频率分别为28%、35%、10%、0%、17%、21%、14%、14%、7%和0%，MM患者中分别为36%、29%、27%、27%、22%、15%、15%、9%、4%和0%。79%的MGUS患者和80%的MM患者检测到这些基因中至少1个基因的甲基化。虽然MGUS患者未检测到ECAD甲基化，但在MM患者中经常观察到，在PCL患者中频率更高。值得注意的是，在MM患者中发现ECAD甲基化与不良预后标志物之间存在关联。
结论
在单克隆丙种球蛋白病患者中可频繁检测到某些基因的甲基化。目前的数据表明，ECAD甲基化是MM和PCL患者疾病进展的标志物。
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