Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff CF144XN, UK.
Hum Mutat. 2008 Aug;29(8):E103-11. doi: 10.1002/humu.20793.
Neurofibromatosis type 1 (NF1), a common autosomal dominant neurogenetic disorder affecting 1 in 4000 individuals worldwide, results from functional inactivation of the 17q11.2-located NF1 gene. Plexiform neurofibroma (PNF) is a congenital benign tumour present in 30-50% of NF1 patients, which in about 10-15% of cases, can develop into a malignant peripheral nerve sheath tumour (MPNST). This study aimed to characterise the NF1 germline and somatic mutations associated with such tumours by DNA analysis in 51 PNFs resected from 44 unrelated NF1 patients. Germline mutations were identified in 35 patients, of which 21 were novel. Somatic NF1 mutations were found in 29 PNF DNAs, which included 9 point mutations, 5 being novel, and 20 tumour DNA samples exhibiting, either loss of heterozygosity (LOH) of the NF1 gene region (16 tumours), or complete or partial NF1 gene deletions analyzed by multiplex ligation-dependent probe amplification (MPLA) analysis. The type of NF1 germline mutations detected in patients with PNF were similar to those detected in most NF1 patients. LOH of the NF1 gene region, as identified by marker analysis and/or MLPA, was detected in only 20/29 (69%) PNFs, compared to the >90% LOH previously found in MPNST. This systematic analysis of the NF1 germline and somatic mutations associated with PNF development suggest that in most such tumours neither the NF1 somatic mutation type, nor its gene location, is influenced by the underlying NF1 germline mutation. Evidence for LOH involving the TP53 gene identified in the PNFs is also reported for the first time.
神经纤维瘤病 1 型（NF1）是一种常见的常染色体显性遗传性神经发育障碍，全球每 4000 人中就有 1 人受到影响，它是由位于 17q11.2 位置的 NF1 基因功能失活引起的。丛状神经纤维瘤（PNF）是一种先天性良性肿瘤，存在于 30-50%的 NF1 患者中，其中约 10-15%的患者会发展成恶性周围神经鞘瘤（MPNST）。本研究旨在通过对 44 名 NF1 患者中切除的 51 个 PNF 进行 DNA 分析，来描述与这些肿瘤相关的 NF1 种系和体细胞突变。在 35 名患者中鉴定出种系突变，其中 21 个是新的。在 29 个 PNF DNA 中发现了体细胞 NF1 突变，其中包括 9 个点突变，其中 5 个是新的，20 个肿瘤 DNA 样本表现出 NF1 基因区域的杂合性丢失（LOH）（16 个肿瘤），或通过多重连接依赖性探针扩增（MLPA）分析发现的 NF1 基因完全或部分缺失。在 PNF 患者中检测到的 NF1 种系突变类型与在大多数 NF1 患者中检测到的类型相似。通过标记分析和/或 MLPA 检测到的 NF1 基因区域 LOH 仅在 29/29（69%）的 PNF 中检测到，而之前在 MPNST 中发现的 LOH 超过 90%。对与 PNF 发展相关的 NF1 种系和体细胞突变的系统分析表明，在大多数此类肿瘤中，无论是 NF1 体细胞突变类型还是其基因位置，都不受潜在 NF1 种系突变的影响。首次报道了在 PNF 中也存在涉及 TP53 基因的 LOH 的证据。
