Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.
BMC Med. 2013 Apr 23;11:109. doi: 10.1186/1741-7015-11-109.
Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome characterized by the development of benign nerve-sheath tumors, which transform to malignant peripheral nerve-sheath tumors (MPNST) in about 8 to 13% of patients with NF1. MPNST are invasive sarcomas with extremely poor prognosis, and their development may correlate with internal tumor load of patients with NF1. Because early identification of patients with NF1 at risk for developing MPNST should improve their clinical outcome, the aim of this study was to identify serum biomarkers for tumor progression in NF1, and to analyze their correlation with tumor type and internal tumor load.
We selected candidate biomarkers for NF1 by manually mining published data sources, and conducted a systematic screen of 56 candidate serum biomarkers using customized antibody arrays. Serum from 104 patients with NF1 with and without MPNST, and from 41 healthy control subjects, was analyzed. Statistical analysis was performed using the non-parametric Mann-Whitney U-test, followed by Bonferroni correction.
Our analysis identified four markers (epidermal growth factor receptor, interferon-γ, interleukin-6, and tumor necrosis factor-α) for which significantly different serum concentrations were seen in patients with NF1 compared with healthy controls. Two markers (insulin-like growth factor binding protein 1 (IGFBP1) and regulated upon activation, normal T-cell expressed and secreted (RANTES)) showed significantly higher concentrations in patients with NF1 and MPNST compared with patients with NF1 without MPNST. A correlation with internal tumor load was found for IGFBP1.
Our study identified two serum markers with potential for early detection of patients with NF1 at risk for developing MPNST, and four markers that could distinguish between patients with NF1 and healthy subjects. Such markers may be useful as diagnostic tools to support the diagnosis of NF1 and for timely identification of MPNST. Moreover, the data suggest that there is a systemic increase in inflammatory cytokines independently of tumor load in patients with NF1.
神经纤维瘤病 1 型（NF1）是一种遗传性肿瘤综合征，其特征为良性神经鞘瘤的发展，约 8-13%的 NF1 患者的神经鞘瘤会转化为恶性外周神经鞘瘤（MPNST）。MPNST 是一种侵袭性肉瘤，预后极差，其发展可能与 NF1 患者的内部肿瘤负荷相关。因为早期识别有发生 MPNST 风险的 NF1 患者应能改善其临床结局，所以本研究旨在鉴定 NF1 中用于肿瘤进展的血清生物标志物，并分析其与肿瘤类型和内部肿瘤负荷的相关性。
我们通过手动挖掘已发表的数据源来选择 NF1 的候选生物标志物，并使用定制的抗体阵列对 56 种候选血清生物标志物进行了系统筛选。分析了 104 例 NF1 伴或不伴 MPNST 患者和 41 例健康对照者的血清。使用非参数 Mann-Whitney U 检验进行统计分析，然后进行 Bonferroni 校正。
我们的分析鉴定了 4 种标志物（表皮生长因子受体、干扰素-γ、白细胞介素-6 和肿瘤坏死因子-α），与健康对照组相比，NF1 患者的血清浓度存在显著差异。2 种标志物（胰岛素样生长因子结合蛋白 1（IGFBP1）和激活正常 T 细胞表达和分泌（RANTES））在 NF1 伴 MPNST 患者中的浓度明显高于 NF1 无 MPNST 患者。与内部肿瘤负荷存在相关性的是 IGFBP1。
我们的研究鉴定了两种具有用于早期检测有发生 MPNST 风险的 NF1 患者的潜力的血清标志物，以及 4 种可用于区分 NF1 患者与健康受试者的标志物。这些标志物可用作诊断工具，支持 NF1 的诊断，并及时识别 MPNST。此外，这些数据表明，NF1 患者存在与肿瘤负荷无关的全身性炎症细胞因子增加。
