Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas.
Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas.
复制标题
DOI：
--
复制
发表时间：
1997-08
期刊：
影响因子：
11.2
通讯作者：
M. Schutte;R. Hruban;J. Geradts;R. Maynard;W. Hilgers;S. Rabindran;C. Moskaluk;S. Hahn;Irmgard Schwa
中科院分区：
文献类型：
--
作者：
M. Schutte;R. Hruban;J. Geradts;R. Maynard;W. Hilgers;S. Rabindran;C. Moskaluk;S. Hahn;Irmgard Schwa
Rb/p16肿瘤抑制途径在人类肿瘤中经常被废除，或者通过Rb或p16 INK 4a/CDKN 2/MTS 1肿瘤抑制蛋白的失活，或者通过细胞周期蛋白D1或细胞周期蛋白依赖性激酶4癌蛋白的改变或过表达。我们以前报道过82%的胰腺癌中p16基因是遗传失活的。这些失活的近一半是由p16基因内突变，其余的是由基因的纯合缺失。在这里，我们分析了胰腺癌的其他机制，Rb/p16通路可能被灭活。应用甲基化特异性PCR检测了18例胰腺癌中p16基因转录沉默及其5 '-CpG岛甲基化。其中9个已知在p16中具有基因内突变，9个具有野生型p16编码序列。18个肿瘤中有7个是高甲基化的，所有7个都是p16野生型（P = 0.001）。证明了甲基化野生型基因序列的转录完全沉默。免疫组化分析显示Rb蛋白在所有研究的癌中的正常表达水平。没有一个癌细胞有细胞周期蛋白D1或CDK 4基因的基因组扩增，也没有一个有CDK 4的p16结合结构域的突变。发现了另外一个p16突变。总的来说，Rb/p16通路废除49 50癌（98%）的研究，所有通过失活的p16基因。在一个独立分析的19例胰腺癌的系列中获得了类似的结果。这些数据表明Rb/p16通路在胰腺癌的发展中的中心作用。
The Rb/p16 tumor-suppressive pathway is abrogated frequently in human tumors, either through inactivation of the Rb or p16INK4a/CDKN2/MTS1 tumor-suppressor proteins, or through alteration or overexpression of the cyclin D1 or cyclin-dependent kinase 4 oncoproteins. We reported previously that the p16 gene was genetically inactivated in 82% of pancreatic carcinomas. Nearly half of these inactivations were by intragenic mutation of p16, and the remainder were by homozygous deletion of the gene. Here, we analyzed pancreatic carcinomas for additional mechanisms by which the Rb/p16 pathway might be inactivated. Transcriptional silencing of the p16 gene in association with methylation of its 5'-CpG island was examined by methylation-specific PCR in 18 pancreatic carcinomas. Nine of these were known to harbor an intragenic mutation in p16, and nine had a wild-type p16 coding sequence. Seven of the 18 tumors were hypermethylated, and all 7 were p16 wild-type (P = 0.001). Complete silencing of transcription from methylated wild-type gene sequences was demonstrated. Immunohistochemical analysis revealed normal expression levels of the Rb protein in all carcinomas studied. None of the carcinomas had genomic amplification of the cyclin D1 or CDK4 genes, and none had mutation of the p16-binding domain of CDK4. An additional p16 mutation was identified. In total, the Rb/p16 pathway was abrogated in 49 of the 50 carcinomas (98%) studied, all through inactivation of the p16 gene. Similar results were obtained in an independently analyzed series of 19 pancreatic carcinomas. These data demonstrate the central role of the Rb/p16 pathway in the development of pancreatic carcinoma.