Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation
Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation
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DOI：
10.1016/s0002-9440(10)65507-1
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发表时间：
1999-12-01
影响因子：
6
通讯作者：
Louis, DN
中科院分区：
文献类型：
--
作者：
Nielsen, GP;Stemmer-Rachamimov, AO;Louis, DN
神经纤维瘤病1型（NF1）患者易发展为多发性神经纤维瘤（NFs），并有nf向恶性周围神经鞘肿瘤（mpnst）转化的风险。然而，关于NFs恶性转化所涉及的生物学事件知之甚少。我们在NF1患者的NFs和MPNSTs中检测了CDKN2A/p16基因和p16蛋白。免疫组化分析显示，所有NFs均表达p16蛋白。然而，mpnst对p16基本上是免疫阴性的，在包含良性和恶性元素的病例中有显著的转变。这些良性肿瘤中没有CDKN2A/p16缺失，而6个mpnst中有3个似乎具有纯合子CDKN2A/p16缺失。CDKN2A/p16在MPNSTs中的甲基化分析和突变分析未发现任何异常。这些结果表明，NF的恶性转化与p16表达的缺失有关，而p16表达的缺失通常继发于CDKN2A/ p16基因的纯合缺失。研究结果表明，CDKN2A/p16失活发生在NF1患者的NFs恶性转化过程中，并提出了p16免疫组织化学可能为区分NF和MPNST提供辅助信息的可能性。
Patients with neurofibromatosis 1 (NF1) are predisposed to develop multiple neurofibromas (NFs) and are at risk for transformation of NFs to malignant peripheral nerve sheath tumors (MPNSTs). Little is known, however, about the biological events involved in the malignant transformation of NFs. We examined the CDKN2A/p16 gene and p16 protein in NFs and MPNSTs from patients with NF1. On immunohistochemical analysis, all NFs expressed p16 protein. The MPNSTs, however, were essentially immunonegative for p16, with striking transitions in cases that contained both benign and malignant elements. None of the benign tumors had CDKN2A/p16 deletions, whereas three of six MPNSTs appeared to have homozygous CDKN2A/p16 deletions. Methylation analysis and mutation analysis of CDKN2A/p16 in MPNSTs did not reveal any abnormalities. These results show that malignant transformation of NF is associated with loss of p16 expression, which is often secondary to homozygous deletion of the CDKN2A/ p16 gene. The findings suggest that CDKN2A/p16 inactivation occurs during the malignant transformation of NFs in NF1 patients and raises the possibility that p16 immunohistochemistry may provide ancillary information in the distinction of NF from MPNST.