Weihrauch Markus, Markwarth Anett, Lehnert Gerhard, Wittekind Christian, Wrbitzky Renate, Tannapfel Andrea
Institute of Occupational Medicine, University of Hannover, Germany.
Hum Pathol. 2002 Sep;33(9):884-92. doi: 10.1053/hupa.2002.126880.
The INK4a-ARF locus, located on chromosome 9p21, encodes 2 cell cycle-regulatory proteins, p16(INKa) and p14(ARF), acting through the Rb-CDK4 and p53 pathways. This study was done to investigate the contribution of the INK4a-ARF locus in tumorigenesis of angiosarcoma of the liver. Alterations of p14(ARF), p16(INKa), and p53 in primary liver angiosarcoma from 19 patients were analyzed by methylation-specific polymerase chain reaction (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR), microsatellite analysis, and DNA sequencing. As a control group, 12 angiosarcomas from other organs were analyzed. Promoter methylation of p14(ARF) was found in 5 of 19 cases (26%), and p16(INKa) showed aberrant promoter methylation in 12 of 19 cases (63%). One tumor (5%) had homozygous deletion of the INK4a-ARF locus. Methylation and deletion correlated with loss of mRNA transcription. Methylated p14(ARF) appeared in the context of a methylated p16(INKa) promoter in 3 cases of the 5 angiosarcomas methylated at p14(ARF). p14(ARF) aberrant methylation was not related to the presence of p53 mutations, which was detected in 6 of 19 (32%) cases. Alterations of the INK4a-ARF locus or p53 as were not established independent prognostic factors in these tumors. In conclusion, our data indicate that the INK4a-ARF locus is frequently inactivated in angiosarcoma of the liver and occurs independently of p53 mutations.
位于9号染色体p21的INK4a - ARF基因座编码两种细胞周期调节蛋白，即p16(INKa)和p14(ARF)，它们通过Rb - CDK4和p53途径发挥作用。本研究旨在探讨INK4a - ARF基因座在肝血管肉瘤发生中的作用。采用甲基化特异性聚合酶链反应(MSP)、限制性内切酶相关聚合酶链反应(RE - PCR)、微卫星分析和DNA测序技术，分析了19例原发性肝血管肉瘤中p14(ARF)、p16(INKa)和p53的改变情况。作为对照组，分析了12例来自其他器官的血管肉瘤。19例中有5例(26%)发现p14(ARF)启动子甲基化，19例中有12例(63%)显示p16(INKa)启动子异常甲基化。1个肿瘤(5%)发生INK4a - ARF基因座纯合缺失。甲基化和缺失与mRNA转录缺失相关。在5例p14(ARF)甲基化的血管肉瘤中，有3例甲基化的p14(ARF)出现在甲基化的p16(INKa)启动子背景下。p14(ARF)异常甲基化与p53突变无关，19例中有6例(32%)检测到p53突变。INK4a - ARF基因座或p53的改变并不是这些肿瘤独立的预后因素。总之，我们的数据表明，INK4a - ARF基因座在肝血管肉瘤中经常失活，且独立于p53突变发生。
