{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:37:57Z","timestamp":1790181477197,"version":"4.1.0"},"reference-count":99,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Emma ed Ernesto Rulfo per la Genetica Medica"},{"name":"\u201cFIL-BANDO DI ATENEO PER LA RICERCA 2022\u201d from University of Parma"},{"name":"European Union\u2014Next Generation EU","award":["PNRR-M4C2- I1.1"],"award-info":[{"award-number":["PNRR-M4C2- I1.1"]}]},{"name":"European Union\u2014Next Generation EU","award":["Bando PRIN 2022 PNRR"],"award-info":[{"award-number":["Bando PRIN 2022 PNRR"]}]},{"name":"European Union\u2014Next Generation EU","award":["P2022M9SRW"],"award-info":[{"award-number":["P2022M9SRW"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Neurofibromatosis type 1 (NF1) predisposes to a spectrum of peripheral nerve sheath tumors, ranging from benign plexiform neurofibromas (PN) to atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP) and malignant peripheral nerve sheath tumors (MPNST). Tumorigenesis follows a multistep molecular cascade initiated by biallelic NF1 inactivation, followed by CDKN2A loss and disruption of the Polycomb Repressive Complex 2 (PRC2). These events guide chromatin remodeling, widespread epigenetic dysregulation, and activation of oncogenic pathways such as RAS\/MAPK and PI3K\/AKT. Here, we integrate genomic, transcriptomic, and epigenomic studies to delineate the molecular trajectories underlying tumor progression and to define promising biomarkers for the early detection of malignant transformation. Emerging liquid biopsy approaches, based on circulating tumor DNA (ctDNA) analyses, reveal distinctive copy number variations (CNVs) and methylation patterns that mirror tissue-derived profiles, enabling the detection of malignant transformation. Together, these findings support a model in which cumulative genetic and epigenetic alterations drive the PN\u2013ANNUBP\u2013MPNST continuum. They also underscore the value of multi-omics and liquid biopsy-based strategies to improve early diagnosis, patient risk stratification, and personalized management of NF1-associated tumors, thereby advancing precision medicine in this complex disease spectrum.<\/jats:p>","DOI":"10.3390\/cancers17243955","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T11:17:27Z","timestamp":1765451847000},"page":"3955","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Pathogenesis of the Neurofibroma-to-Sarcoma Transition in Neurofibromatosis Type I: From Molecular Profiles to Diagnostic Applications"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4509-7694","authenticated-orcid":false,"given":"Sabrina","family":"Busciglio","sequence":"first","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6816-6131","authenticated-orcid":false,"given":"Ilenia Rita","family":"Cannizzaro","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Luberto","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4282-6801","authenticated-orcid":false,"given":"Antonietta","family":"Taiani","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Moschella","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Ambrosini","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Cesarini","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9175-9455","authenticated-orcid":false,"given":"Mirko","family":"Treccani","sequence":"additional","affiliation":[{"name":"Department of Food and Drug, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Azzoni","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Bottarelli","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Corradi","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Uliana","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-7031","authenticated-orcid":false,"given":"Davide","family":"Martorana","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7711-2156","authenticated-orcid":false,"given":"Valeria","family":"Barili","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3268-6786","authenticated-orcid":false,"given":"Antonio","family":"Percesepe","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/S1474-4422(14)70063-8","article-title":"Neurofibromatosis Type 1: A Multidisciplinary Approach to Care","volume":"13","author":"Hirbe","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_2","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. 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