CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated.
CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated.
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发表时间：
1996
期刊：
影响因子：
11.2
通讯作者：
K. Ueki;Y. Ono;J. Henson;J. Efird;A. Deimling;D. Louis
中科院分区：
文献类型：
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作者：
K. Ueki;Y. Ono;J. Henson;J. Efird;A. Deimling;D. Louis
p16参与细胞周期调控级联反应，包括细胞周期蛋白依赖性激酶4（cdk 4）、细胞周期蛋白D1和pRb（视网膜母细胞瘤）。在原发性人多形性胶质母细胞瘤（GBM）或GBM细胞系中已经描述了这些组分中的每一种的改变。因为在这一途径中的任何组件的扰动可能有类似的致癌作用，我们研究了CDKN 2/p16和RB，两个常见的肿瘤抑制基因，在55个星形胶质细胞瘤（42 GBM，8间变性星形细胞瘤，5星形细胞瘤）的异常之间的关系。通过使用比较多重PCR，在24例GBM（57%）和2例间变性星形细胞瘤中检测到CDKN 2/p16基因纯合缺失。另外两个GBM和一个间变性星形细胞瘤有染色体9 p等位基因丢失，通过CDKN 2/p16区域侧翼的微卫星多态性进行评估。单链构象多态性和DNA测序分析的所有三个编码外显子的CDKN 2/p16揭示了移码突变（4个碱基缺失）在三个GBM中的一个已经失去了其余的9 p等位基因。在14例GBM（33%）和2例间变性星形细胞瘤中发现了RB基因13 q等位基因缺失、RB基因突变或pRb表达缺失。42例GBM中有36例（86%）存在CDKN 2/p16（n = 22）、RB（n = 10）或两者（n = 4）的改变;然而，这两种遗传变化相对排他性（P = 0.003）。此外，在6例无CDKN 2/p16或RB基因异常的GBM中，1例有CDK 4基因扩增。这些数据表明，绝大多数GBM可能具有p16-cdk 4/细胞周期蛋白D1-pRb通路的失活。这些发现也为CDKN 2/p16和RB分别是染色体9 p和13 q上的关键胶质瘤肿瘤抑制基因提供了确凿的证据。
p16 is involved in a cell cycle regulatory cascade that includes cyclin-dependent kinase 4 (cdk4), cyclin D1, and pRb (retinoblastoma). Alterations of each of these components have been described in primary human glioblastoma multiforme (GBM) or in GBM cell lines. Because perturbation of any component in this pathway may have similar oncogenic effects, we studied the relationship between abnormalities of CDKN2/p16 and RB, the two commonly involved tumor suppressor genes, in 55 astrocytic gliomas (42 GBMs, 8 anaplastic astrocytomas, and 5 astrocytomas). By using comparative multiplex PCR, homozygous deletions of the CDKN2/p16 gene were detected in 24 GBMs (57%) and in 2 anaplastic astrocytomas. Two additional GBMs and one anaplastic astrocytoma had allelic loss of chromosome 9p, as assessed by microsatellite polymorphisms flanking the CDKN2/p16 region. Single-strand conformation polymorphism and DNA sequencing analysis of all three coding exons of CDKN2/p16 revealed a frameshift mutation (four-bp deletion) in one of the three GBMs that had lost the remaining 9p allele. Allelic loss of chromosome 13q at the RB gene, RB gene mutations, or loss of pRb expression was noted in 14 GBMs (33%) and 2 anaplastic astrocytomas. Thirty-six of 42 GBMs (86%) had alterations of either CDKN2/p16 (n = 22), RB (n = 10), or both (n = 4); these two genetic changes, however, were relatively exclusive (P = 0.003). Furthermore, of the six GBMs without either CDKN2/p16 or RB gene abnormalities, one case had CDK4 gene amplification. These data indicate that the vast majority of GBMs probably have inactivation of the p16-cdk4/cyclin D1-pRb pathway. The findings also provide corroborative evidence that CDKN2/p16 and RB are the critical glioma tumor suppressor genes on chromosomes 9p and 13q, respectively.