Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. In orbitofacial neurofibromatosis type 1, NFs may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We used Illumina Methylation EPIC BeadChip to study DNA methylation differences between orbitofacial NFs (N = 20) and NFs at other sites (N = 4). Global methylation differences were detected between the two groups and the top differentially methylated genes were part of the HOX (Homebox) family of transcription factors (HOXC8, HOXC4, HOXC6, HOXA6 and HOXD4), which were hypomethylated in orbitofacial NFs compared to the non-orbital NFs. Conversely, LTF (lactoferrin) was relatively hypermethylated in orbitofacial NF compared to non-orbitofacial NF. HOXC8 protein levels were higher in orbitofacial plexiform NFs (p = 0.04). We found no significant differences in the expression of HOXC4, HOXA6, or HOXD4 between the two groups. HOXC8 mRNA levels were also higher in orbitofacial NFs and HOXC8 overexpression in a non-neoplastic human Schwann cell line resulted in increased growth. In summary, we identified gene methylation and expression differences between orbitofacial NF and NFs occurring at other locations. Further investigation may be warranted, given that the HOX family of genes play an important role during development, are dysregulated in a variety of cancers, and may provide novel insights into therapeutic approaches.

中文翻译：

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眼眶面部神经纤维瘤差异基因甲基化及 HOX 转录因子家族表达


虽然神经纤维瘤 (NF) 最常见的是良性，但除了可能发生恶变之外，还可能对功能和美观产生破坏性影响。在 1 型眼眶面部神经纤维瘤病中，神经纤维瘤可能会导致眼睑、额头、太阳穴、面部和眼眶出现进行性、毁容性肿瘤。本研究的目的是确定眼眶面部神经纤维瘤和发生在其他解剖部位的神经纤维瘤之间的生物学差异。我们使用 Illumina 甲基化 EPIC BeadChip 来研究眼眶面部 NF (N = 20) 和其他位点 NF (N = 4) 之间的 DNA 甲基化差异。检测到两组之间的整体甲基化差异，最高差异甲基化基因是 HOX (Homebox) 转录因子家族（HOXC8、HOXC4、HOXC6、HOXA6 和 HOXD4）的一部分，与非组相比，这些基因在眼眶面部 NF 中甲基化程度较低。轨道 NF。相反，与非眼眶面 NF 相比，眼眶面 NF 中的 LTF（乳铁蛋白）相对高度甲基化。 HOXC8 蛋白水平在眶面丛状神经纤维中较高 (p = 0.04)。我们发现两组之间 HOXC4、HOXA6 或 HOXD4 的表达没有显着差异。 HOXC8 mRNA 水平在眼眶面部 NF 中也较高，并且在非肿瘤性人雪旺细胞系中 HOXC8 过表达导致生长加快。总之，我们确定了眼眶面部 NF 和其他位置发生的 NF 之间的基因甲基化和表达差异。鉴于 HOX 基因家族在发育过程中发挥重要作用，在多种癌症中失调，并且可能为治疗方法提供新的见解，因此可能需要进一步研究。