Mateos M V, Garcia-Sanz R, López-Pérez R, Balanzategui A, González M I, Fernández-Calvo J, Moro M J, Hernández J, Caballero M D, González M, San Miguel J F
Hematology Service, University Hospital of Salamanca, Spain.
Hematol J. 2001;2(3):146-9. doi: 10.1038/sj.thj.6200084.
A model of a stepwise malignant transformation has been proposed for the pathogenesis of monoclonal gammopathies. In this model, cell cycle regulators play a central role as a source of genetic events; particularly, p16/INK4a gene acts as a tumoral suppressor gene and, recently, inactivation of this gene through a methylation mechanism, has been observed in multiple myeloma patients. Under the diagnosis of monoclonal gammopathies there is a broad spectrum of disorders with very different outcomes, ranging from indolent courses, such as those of monoclonal gammopathy of undetermined significance, Waldeströn macroglobulinemia and smoldering multiple myeloma, to aggressive diseases such as symptomatic MM and primary plasma cell leukemia. To the best of our knowledge, the activity of p16 gene has not been evaluated and compared in these different subtypes of monoclonal gammopathies.
The methylation status of the p16 gene was analysed in a group of 159 patients with monoclonal gammopathies (40 monoclonal gammopathy of uncertain significance, eight Waldenström Macroglobulinemia, eight smoldering multiple myeloma, 98 symptomatic multiple myeloma and five primary plasma cell leukemia) using three different assays (restriction enzymes and PCR or S-B and modification by sodium bisulphite).
Forty-one of 98 MM patients (41.8%) as well as four of the five (80%) primary PCL patients showed methylation of the p16 gene, while none of the patients with monoclonal gammopathy of undetermined significance, Waldenström Macroglobulinemia or smoldering multiple myeloma displayed a methylation status.
These findings suggest that the methylation of the p16 gene could be a relevant oncogenic event in the monoclonal gammopathies evolution being associated with the most aggressive forms.
已提出一种逐步恶性转化模型用于解释单克隆丙种球蛋白病的发病机制。在该模型中，细胞周期调节因子作为遗传事件的来源发挥核心作用；特别是，p16/INK4a基因作为肿瘤抑制基因，最近在多发性骨髓瘤患者中观察到该基因通过甲基化机制失活。在单克隆丙种球蛋白病的诊断中，存在一系列结局差异很大的疾病，从惰性病程，如意义未明的单克隆丙种球蛋白病、华氏巨球蛋白血症和冒烟型多发性骨髓瘤，到侵袭性疾病，如症状性骨髓瘤和原发性浆细胞白血病。据我们所知，尚未在这些不同亚型的单克隆丙种球蛋白病中评估和比较p16基因的活性。
使用三种不同检测方法（限制性内切酶和聚合酶链反应或亚硫酸氢盐修饰）分析了一组159名单克隆丙种球蛋白病患者（40例意义未明的单克隆丙种球蛋白病、8例华氏巨球蛋白血症、8例冒烟型多发性骨髓瘤、98例症状性多发性骨髓瘤和5例原发性浆细胞白血病）中p16基因的甲基化状态。
98例骨髓瘤患者中有41例（41.8%）以及5例原发性浆细胞白血病患者中有4例（80%）显示p16基因甲基化，而意义未明的单克隆丙种球蛋白病、华氏巨球蛋白血症或冒烟型多发性骨髓瘤患者均未显示甲基化状态。
这些发现表明，p16基因甲基化可能是单克隆丙种球蛋白病演变过程中与最具侵袭性形式相关的一个重要致癌事件。
