Prospects for epigenetic research in neurofibromatosis type 1

Background. Neurofibromatosis type 1 (NF1) is a monogenic disease with a wide range of clinical manifestations. NF1 is associated with increased risk of malignant peripheral nerve sheath tumors (MPNST), leukemia, gastrointestinal and breast cancer, rhabdomyosarcoma, carcinoid tumors, and pheochromocytoma. NF1 gene mutations serve as drivers of various sporadic malignancies. the purpose of the study was to evaluate the mechanisms by which epigenetic factors influence the development of NF1 and the potential for their use in diagnosis and treatment.

Material and Methods. The search for relevant sources was carried out in Scopus, Web of Science, PubMed, Elibrary, including publications from February 1995 to February 2025. Of the 1432 scientific articles found, 56 were used to write the review.

Results. An analysis of scientific literature showed that NF1 mRNA is a target of 13 microRNAs that are also involved in carcinogenesis of sporadic nervous system tumors (miR-9, miR-10b, miR-16, miR-21, miR-27a, miR-27b-3p, miR-34a, miR125a-3p, miR-128-3p, miR-137-3p, miR-147a, miR-193b, miR-204-5p). There is evidence of an evolutionary and functional relationship between NF1 gene and retroelements: the formation of 12 NF1 pseudogenes on 7 different chromosomes with the help of retroelement enzymes, NF1 introns contain Alu and LINE, which are sources of alternative splicing and recombination, and the presence of insertional mutagenesis hot spots in NF1.

Conclusion. Genetic studies have not confirmed the role of modifier genes as triggers for the development and progression of tumor syndrome in NF1. However, changes in the expression of specific microRNAs have been identified in the development of cutaneous, subcutaneous, and plexiform neurofibromas, MPNST. This suggests the potential of studying of epigenetic factors in NF1 pathogenesis for targeted therapy. Further studies of the relationship between the NF1 gene and retroelements will identify new treatment options for NF1 and sporadic tumors by addressing the “vicious cycle” described in the relationship between other tumor suppressor genes and retroelements.

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