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Plasma DNA Methylation-Based Biomarkers for MPNST Detection in Patients With Neurofibromatosis Type 1
Katarzyna Tomczak1,2, Manishkumar S Patel3, Angela D Bhalla1
1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Molecular Carcinogenesis
|November 27, 2024
Summary
Researchers identified 73 specific DNA methylation sites (CpGs) that distinguish malignant peripheral nerve sheath tumors (MPNST) from neurofibromas. These biomarkers show promise for early MPNST detection in neurofibromatosis type 1 (NF1) patients using blood plasma.
Area of Science:
- Oncology
- Genetics
- Biomarker Discovery
Background:
- Malignant peripheral nerve sheath tumors (MPNST) are aggressive cancers often arising in patients with neurofibromatosis type 1 (NF1).
- Altered DNA methylation patterns are implicated in MPNST development, suggesting potential for diagnostic biomarkers.
- Early detection of MPNST in NF1 patients is crucial for improving outcomes.
Purpose of the Study:
- To identify and validate MPNST-specific DNA methylation biomarkers for early detection.
- To assess the utility of these biomarkers in both tumor tissues and cell-free DNA (cfDNA) from plasma.
- To differentiate MPNST from benign neurofibromas and identify malignant transformation in NF1 patients.
Main Methods:
- Genome-wide DNA methylation profiling of MPNST tissues, adjacent neurofibromas, and NF1-MPNST cell lines.
- Logistic regression modeling to select MPNST-specific CpG sites.
- Cell-free DNA Methylation Capture Sequencing (cfMBD-seq) to analyze plasma cfDNA methylomes.
- Validation of candidate biomarkers in tissue and plasma samples.
Main Results:
- Identified 73 candidate MPNST-specific CpG sites, with 67 located in unique CpG islands, effectively discriminating MPNSTs from neurofibromas.
- Tissue validation of five biomarkers achieved high sensitivity (>88%) and specificity (>91%) for MPNST detection.
- Plasma cfDNA analysis revealed significantly higher methylation in 63 of 67 selected regions in MPNST patients compared to NF1 patients.
- Identified 15 CpG islands that consistently differentiated plasma of MPNST patients from individuals with NF1 without malignant transformation (FDR < 0.1).
Conclusions:
- A unique DNA hypermethylation pattern is associated with malignant transformation in MPNST.
- The identified CpG sites hold significant potential as non-invasive biomarkers for early MPNST detection in NF1 patients.
- Further clinical investigation of these plasma-based biomarkers is warranted for routine screening.
