Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Hum Genomics. 2012 Sep 4;6(1):18. doi: 10.1186/1479-7364-6-18.
Neurofibromatosis type-1 (NF1), resulting from NF1 gene loss of function, is characterized by an increased risk of developing benign and malignant peripheral nerve sheath tumors (MPNSTs). Whereas the cellular heterogeneity of NF1-associated tumors has been well studied, the molecular heterogeneity of MPNSTs is still poorly understood. Mutational heterogeneity within these malignant tumors greatly complicates the study of the underlying mechanisms of tumorigenesis. We have explored this molecular heterogeneity by performing loss of heterozygosity (LOH) analysis of the NF1, TP53, RB1, PTEN, and CDKN2A genes on sections of 10 MPNSTs derived from 10 unrelated NF1 patients. LOH data for the TP53 gene was found to correlate with the results of p53 immunohistochemical analysis in the same tumor sections. Further, approximately 70% of MPNSTs were found to display intra-tumoral molecular heterogeneity as evidenced by differences in the level of LOH between different sections of the same tumor samples. This study constitutes the first systematic analysis of molecular heterogeneity within MPNSTs derived from NF1 patients. Appreciation of the existence of molecular heterogeneity in NF1-associated tumors is important not only for optimizing somatic mutation detection, but also for understanding the mechanisms of NF1 tumorigenesis, a prerequisite for the development of specifically targeted cancer therapeutics.
神经纤维瘤病 1 型（NF1）是由 NF1 基因功能丧失引起的，其特征是良性和恶性周围神经鞘肿瘤（MPNST）的发病风险增加。虽然 NF1 相关肿瘤的细胞异质性已经得到了很好的研究，但 MPNST 的分子异质性仍知之甚少。这些恶性肿瘤中的突变异质性极大地增加了对肿瘤发生潜在机制的研究的复杂性。我们通过对 10 名 NF1 患者的 10 个 MPNST 样本的切片进行 NF1、TP53、RB1、PTEN 和 CDKN2A 基因的杂合性丢失（LOH）分析，来探索这种分子异质性。TP53 基因的 LOH 数据与同一肿瘤切片中 p53 免疫组化分析的结果相关。此外，大约 70%的 MPNST 显示出肿瘤内分子异质性，这表现为同一肿瘤样本的不同切片之间 LOH 水平的差异。这项研究构成了对 NF1 患者来源的 MPNST 内分子异质性的首次系统分析。了解 NF1 相关肿瘤中存在分子异质性不仅对于优化体细胞突变检测很重要，而且对于理解 NF1 肿瘤发生的机制也很重要，这是开发特异性靶向癌症治疗的前提。
