Frequent Loss of the CDKN2C (p18INK4c) Gene Product in Pituitary Adenomas
Frequent Loss of the CDKN2C (p18INK4c) Gene Product in Pituitary Adenomas
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DOI：
10.1002/gcc.20621
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发表时间：
2009-02-01
影响因子：
3.7
通讯作者：
Schackert, Gabriele
中科院分区：
文献类型：
--
作者：
Kirsch, Matthias;Moerz, Michael;Schackert, Gabriele
细胞周期蛋白依赖性激酶抑制剂的基因组改变已在包括脑肿瘤在内的多种肿瘤类型中得到证实。其中，细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A或p16（INK4a））基因已被证明在星形细胞肿瘤中频繁缺失或失活。CDKN2C（p18（INK4c））基因在功能上与CDKN2A相关。此外，单独靶向破坏CDKN 2 C或组合CDKN 2 C和细胞周期蛋白依赖性激酶抑制剂I B（CDKN I B或p27（Kipl））或CDKN 2 C和TP 53基因破坏的小鼠以高频率发生垂体腺瘤（PA）。本研究的目的是通过分析38例PA中的杂合性缺失（洛）、突变筛查、启动子甲基化分析和蛋白表达来研究CDKN 2C基因的遗传改变。此外，研究了细胞周期基因CDKN2A及其可变剪接形式p14（ARF）以及视网膜母细胞瘤RBI基因的基因组改变和蛋白质表达。在25%的垂体腺瘤中检测到CDKN 2C基因位点的洛缺失，而RBI和CDKN 2A基因位点的改变仅占10%。在CDKN2C基因的编码区内未检测到突变。然而，39.5%的腺瘤显示CDKN2C启动子甲基化。CDKN 2 C蛋白的缺失与I号染色体上CDKN 2 C位点的洛缺失和CDKN 2 C启动子的甲基化相关。这是第一个报告，描述了肿瘤抑制基因CDKN2C经常被靶向的基因组改变在垂体腺瘤。最常见的遗传改变是启动子甲基化，这表明CDKN2C的失活可能在垂体腺瘤的发展中起重要作用。其他支持信息可在本文的在线版本中找到。(c)2008威利利斯公司
Genomic alterations of cyclin-dependent kinase inhibitors have been demonstrated in a variety of tumor types including brain tumors. Among them, the cyclin-dependent kinase inhibitor 2A (CDKN2A or p16(INK4a)) gene has been shown to be frequently deleted or inactivated in astrocytic tumors. The CDKN2C (p18(INK4c),) gene is functionally related to CDKN2A. Moreover, mice with targeted disruption of CDKN2C alone or combined CDKN2C and cyclin-dependent kinase inhibitor I B (CDKN I B or p27(Kipl)), or CDKN2C and TP53 gene disruption develop pituitary adenomas (PA) at high frequencies. The purpose of our study was to investigate genetic alterations of the CDKN2C gene by analysis of loss of heterozygosity (LOH), screening for mutations, analysis of promoter methylation, and protein expression in 38 PAs. In addition, genomic alterations and protein expression of the cell cycle genes CDKN2A and its alternatively spliced form, p14(ARF), as well as the retinoblastoma RBI gene were investigated. LOH at the CDKN2C gene locus was detected in 25% of pituitary adenomas, whereas the RBI and CDKN2A loci were altered in only 10%. No mutations were detected within the coding regions of the CDKN2C gene. However, 39.5% of adenomas displayed CDKN2C promoter methylation. The absence of CDKN2C protein was correlated with LOH of the CDKN2C locus on chromosome I and with methylation of the CDKN2C promoter. This is the first report to describe that the tumor suppressor gene CDKN2C is frequently targeted by genomic alterations in pituitary adenoma. The most common genetic alteration was promoter methylation suggesting that inactivation of CDKN2C by this mechanism may play an important role in pituitary adenoma development. Additional Supporting Information may be found in the online version of this article. (c) 2008 Wiley-Liss, Inc.