Plasma DNA Methylation-Based Biomarkers for MPNST Detection in Patients With Neurofibromatosis Type 1

Authors

Katarzyna Tomczak
Manishkumar S Patel
Angela D Bhalla
Christine B Peterson
Sharon M Landers
S Carson Callahan
Di Zhang
Justin Wong
Jace P Landry
Alexander J Lazar
J Andrew Livingston
B Ashleigh Guadagnolo
Heather G Lyu
Heather Lillemoe
Christina L Roland
Emily Z Keung
Christopher P Scally
Kelly K Hunt
Ian E McCutcheon
John M Slopis
Jian Gu
Paul Scheet
Liang Wang
Kunal Rai
Keila E Torres

Publication Date

1-1-2025

Journal

Molecular Carcinogenesis

Abstract

Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST-specific biomarkers for screening patients with NF1. Genome-wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1-MPNST cell lines was performed to identify and validate candidate MPNST-specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST-specific 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-seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature-selection criteria and predictive modeling, we identified 73 candidate MPNST-specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2-fold 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 <  0.1). 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.

Keywords

Humans, DNA Methylation, Neurofibromatosis 1, Biomarkers, Tumor, CpG Islands, Female, Male, Adult, Middle Aged, Neurofibrosarcoma, Cell Line, Tumor, Aged, biomarker, DNA methylation, MPNST, neurofibromatosis type 1, plasma

Comments

This article has been corrected. See Mol Carcinog. 2025 Mar 18.

DOI

10.1002/mc.23825

PMID

39600120

PMCID

PMC11636586

PubMedCentral® Posted Date

11-26-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes