Abstract
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.
Highlights
Neurofibromatosis type 1 (NF1), known as von Recklinghausen disease, is a relatively frequent (1 in 3000 live births), autosomal dominant, neurocutaneous disorder with heterogeneous clinicopathologic manifestations [38]
HOX family of transcription factors are hypomethylated in orbitofacial neurofibromas Differential methylation analysis identified 7 differential methylated regions between the orbitofacial (n = 20) and non-orbitofacial (n = 4) neurofibromas (FWER ≤0.1; P ≤ 0.0001) (Fig. 2 and Table 1)
HOXC8, HOXC4, HOXC6, HOXA6 and HOXD4 were found hypomethylated in the orbitofacial NF compared with the non-ocular (Fig. 3)
Summary
Neurofibromatosis type 1 (NF1), known as von Recklinghausen disease, is a relatively frequent (1 in 3000 live births), autosomal dominant, neurocutaneous disorder with heterogeneous clinicopathologic manifestations [38]. The most prevalent tumor in NF1 patients is neurofibroma (NF), which is typically slow growing and benign, but can have devastating functional and cosmetic effects. Malignant transformation develops in 5–10% of NF1 patients, typically in a plexiform neurofibromas subtype [45]. Orbitofacial neurofibromatosis type 1 (OFNF) has been recognized as a unique clinical variant of NF1 for many years [6]. In OFNF, which occurs in 1–22% of patients, orbitofacial NFs may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit [11, 33, 48]. Large NFs involving the orbit tend to be more aggressive and infiltrative compared to NFs located elsewhere in the body
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