Atypical Neurofibromas in Neurofibromatosis Type 1 are Premalignant Tumors
Atypical Neurofibromas in Neurofibromatosis Type 1 are Premalignant Tumors
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DOI：
10.1002/gcc.20921
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发表时间：
2011-12-01
影响因子：
3.7
通讯作者：
Legius, Eric
中科院分区：
文献类型：
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作者：
Beert, Eline;Brems, Hilde;Legius, Eric
良性周围神经鞘瘤(PNSTs)是神经纤维瘤病I型(NF1)患者的特征。NF1患者一生中患恶性PNST(MPNST)的风险为8-13%。非典型神经纤维瘤是有症状的、细胞增多的PNST，由细胞核深染但无有丝分裂的细胞组成。NF1患者中非典型神经纤维瘤的起源和性质知之甚少。在这项研究中，我们通过分析48名NF1患者的65个肿瘤样本，对NF1相关PNSTs谱中的非典型神经纤维瘤进行了分类。我们通过核型分析和基于微阵列的比较基因组杂交(ACGH)，比较了良性神经纤维瘤、不典型神经纤维瘤和MPNSTs(低、中、高级别)之间肿瘤特异性染色体拷贝数的变化。在15例良性神经纤维瘤(4例皮下神经纤维瘤和11例丛状神经纤维瘤)中，除了1例丛状神经纤维瘤外，没有发现拷贝数改变。在非典型神经纤维瘤中发现了一种高度显著的复发异常(15/16)，即染色体9p21.3带包括CDKN2A和CDKN2B的最小重叠区域(MOR)缺失。CDKN2A/B基因座拷贝数丢失是MPNST组中最常见的事件之一，在低、中、高级别的MPNST中均有缺失。在一个肿瘤中，我们观察到从良性-非典型神经纤维瘤到中级MPNST的明显转变，这一转变得到了组织病理学和a CGH分析的证实。这些数据支持这样的假设，即非典型神经纤维瘤是癌前肿瘤，CDKN2A/B缺失是进展为MPNST的第一步。(C)2011年威利期刊公司。
Benign peripheral nerve sheath tumors (PNSTs) are a characteristic feature of neurofibromatosis type I (NF1) patients. NF1 individuals have an 8-13% lifetime risk of developing a malignant PNST (MPNST). Atypical neurofibromas are symptomatic, hypercellular PNSTs, composed of cells with hyperchromatic nuclei in the absence of mitoses. Little is known about the origin and nature of atypical neurofibromas in NF1 patients. In this study, we classified the atypical neurofibromas in the spectrum of NF1-associated PNSTs by analyzing 65 tumor samples from 48 NF1 patients. We compared tumor-specific chromosomal copy number alterations between benign neurofibromas, atypical neurofibromas, and MPNSTs (low-, intermediate-, and high-grade) by karyotyping and microarray-based comparative genome hybridization (aCGH). In 15 benign neurofibromas (4 subcutaneous and 11 plexiform), no copy number alterations were found, except a single event in a plexiform neurofibroma. One highly significant recurrent aberration (15/16) was identified in the atypical neurofibromas, namely a deletion with a minimal overlapping region (MOR) in chromosome band 9p21.3, including CDKN2A and CDKN2B. Copy number loss of the CDKN2A/B gene locus was one of the most common events in the group of MPNSTs, with deletions in low-, intermediate-, and high-grade MPNSTs. In one tumor, we observed a clear transition from a benign-atypical neurofibroma toward an intermediate-grade MPNST, confirmed by both histopathology and aCGH analysis. These data support the hypothesis that atypical neurofibromas are premalignant tumors, with the CDKN2A/B deletion as the first step in the progression toward MPNST. (C) 2011 Wiley Periodicals, Inc.