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Genome\u2010wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1\u2010MPNST cell lines was performed to identify and validate candidate MPNST\u2010specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST\u2010specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD\u2010seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature\u2010selection criteria and predictive modeling, we identified 73 candidate MPNST\u2010specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: &gt;\u200988%, specificity: &gt;\u200991%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2\u2010fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR\u2009&lt;\u20090.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be investigated further as biomarkers in clinical settings for early MPNST detection in patients with NF1.<\/jats:p>","DOI":"10.1002\/mc.23825","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T06:50:00Z","timestamp":1732690200000},"page":"44-56","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Plasma DNA Methylation\u2010Based Biomarkers for MPNST Detection in Patients With Neurofibromatosis Type 1"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0553-8056","authenticated-orcid":false,"given":"Katarzyna","family":"Tomczak","sequence":"first","affiliation":[{"name":"Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston Texas USA"},{"name":"Department of Genomic Medicine The University of Texas MD Anderson Cancer Center Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2450-0662","authenticated-orcid":false,"given":"Manishkumar S.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Tumor Microenvironment and Metastasis H. 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