{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T09:50:14Z","timestamp":1782899414077,"version":"3.54.5"},"reference-count":125,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Neurofibromatosis type 1 (NF1) is a genetic tumor predisposition syndrome characterized by a substantial risk of developing peripheral nerve sheath tumors, including malignant peripheral nerve sheath tumors (MPNSTs), which occur in 8\u201313% of patients. Approximately 50% arise from plexiform neurofibromas (PNs) and 40% develop de novo, making them a major cause of premature mortality. Current clinical management is limited by the intrinsic shortcomings of standard imaging modalities: magnetic resonance imaging (MRI) and positron emission tomography\/computed tomography (PET\/CT), and tissue biopsy in distinguishing benign PNs from early malignant transformation, which remains a major clinical challenge. This progression follows a stepwise molecular continuum marked by cumulative genetic alterations and widespread epigenetic dysregulation. In this setting, liquid biopsy has emerged as a promising non-invasive approach to help fill these diagnostic gaps by enabling real-time molecular monitoring through the analysis of circulating tumor DNA (ctDNA) and other blood-based biomarkers. This review examines the current evidence supporting liquid biopsy applications in NF1 management, including early detection of MPNST, discrimination between benign and malignant lesions, mutational profiling for therapeutic targeting, and disease monitoring before and during treatment. We also discuss the current evidence on fragmentomics, methylomics and driver mutation profiling as tools to distinguish PNs from MPNSTs. Recent evidence suggests that liquid biopsy may help detect molecular changes associated with malignant transformation before clear clinical signs emerge, potentially opening an important window for intervention and supporting a shift towards a more molecularly informed surveillance model. Finally, this review considers the possible extension of liquid biopsy to other tumor types, including NF1-deficient breast cancer, and outlines a future management framework aimed at improving early diagnosis and personalized therapeutic intervention in this high-risk population.<\/jats:p>","DOI":"10.3390\/diagnostics16132063","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T08:19:02Z","timestamp":1782893942000},"page":"2063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating Tumor DNA in Neurofibromatosis Type 1: Translating Molecular Discovery into Clinical Surveillance"],"prefix":"10.3390","volume":"16","author":[{"given":"Joanne Vanessa","family":"Vargas","sequence":"first","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Tosello","sequence":"additional","affiliation":[{"name":"Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35121 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2397-9852","authenticated-orcid":false,"given":"Giulia","family":"Pigato","sequence":"additional","affiliation":[{"name":"Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35121 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4810-7136","authenticated-orcid":false,"given":"Stefano","family":"Indraccolo","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy"},{"name":"Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35121 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2396-3080","authenticated-orcid":false,"given":"Federica","family":"Chiara","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy"},{"name":"Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35121 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1097\/MS9.0000000000004521","article-title":"Diagnosis, Treatment Management, and Challenges in Neurofibromatosis Type 1: A Case Report with Mixed Features","volume":"88","author":"Liu","year":"2025","journal-title":"Ann. 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