Krämer A, Schultheis B, Bergmann J, Willer A, Hegenbart U, Ho A D, Goldschmidt H, Hehlmann R
Medizinische Klinik und Poliklinik V, Universität Heidelberg, Heidelberg, Germany.
Leukemia. 2002 Sep;16(9):1844-51. doi: 10.1038/sj.leu.2402609.
The retinoblastoma protein (pRb), p16(INK4A), D-type cyclins, and their partners cyclin-dependent kinase (CDK) 4 and 6 constitute a G(1) regulatory pathway commonly targeted in tumorigenesis. Several malignancies show a reciprocal correlation between genetic alterations of single members of the pRb pathway. Therefore, we determined the frequency of Rb deletions and cyclin D1 alterations by fluorescence in situ hybridization as well as 5' CpG island hypermethylation of the p16(INK4A)gene using methylation-specific polymerase chain reaction in bone marrow mononuclear cells from 82 individuals with plasma cell disorders. Alterations in at least one of the components of the pathway were found in 75%. Cyclin D1 translocations or amplifications were detected in 14/82 (17.1%), Rb deletions at 13q14 in 23/82 (28%) of the cases, including three (3.6%) homozygous deletions. p16(INK4A) was hypermethylated in 33/57 (57.9%) of the samples. Further analysis revealed a highly significant correlation between cyclin D1 alterations and extramedullar or leukemic myeloma manifestations (P = 0.014; Fisher's test). Whereas Rb deletions seemed to occur alternatively to cyclin D1 alterations, no reciprocal correlation was found between p16(INK4A) hypermethylations and cyclin D1 or Rb locus aberrations. Cyclin D1 locus alterations and Rb deletions were associated with a significantly worse prognosis whereas p16(INK4A) hypermethylation had no impact on survival. We conclude that cyclin D1 and Rb aberrations seem to occur as alternative events in plasma cell malignancies and contribute to clinical course and prognosis. In contrast, although p16(INK4A) hypermethylation is frequent, inactivation of p16(INK4A) seems not to be involved in the pathogenesis of plasma cell disorders.
视网膜母细胞瘤蛋白（pRb）、p16（INK4A）、D型细胞周期蛋白及其伙伴细胞周期蛋白依赖性激酶（CDK）4和6构成了一条在肿瘤发生过程中常被靶向作用的G1调控通路。几种恶性肿瘤显示出pRb通路单个成员的基因改变之间存在相互关联。因此，我们通过荧光原位杂交确定了Rb缺失和细胞周期蛋白D1改变的频率，并使用甲基化特异性聚合酶链反应检测了82例浆细胞疾病患者骨髓单个核细胞中p16（INK4A）基因的5'CpG岛高甲基化情况。在75%的病例中发现该通路至少一种成分存在改变。在14/82（17.1%）的病例中检测到细胞周期蛋白D1易位或扩增，23/82（28%）的病例存在13q14处的Rb缺失，其中包括3例（3.6%）纯合缺失。在33/57（57.9%）的样本中p16（INK4A）发生了高甲基化。进一步分析显示细胞周期蛋白D1改变与髓外或白血病性骨髓瘤表现之间存在高度显著的相关性（P = 0.014；Fisher检验）。虽然Rb缺失似乎与细胞周期蛋白D1改变交替出现，但未发现p16（INK4A）高甲基化与细胞周期蛋白D1或Rb基因座畸变之间存在相互关联。细胞周期蛋白D1基因座改变和Rb缺失与预后明显较差相关，而p16（INK4A）高甲基化对生存率无影响。我们得出结论，细胞周期蛋白D1和Rb畸变似乎是浆细胞恶性肿瘤中的交替事件，并影响临床病程和预后。相比之下，虽然p16（INK4A）高甲基化很常见，但p16（INK4A）的失活似乎不参与浆细胞疾病的发病机制。
