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DLK1 Distinguishes Subsets of NF1-Associated Malignant Peripheral Nerve Sheath Tumors with Divergent Molecular Signatures

Study Design and Aims

We aimed to investigate the molecular mechanisms underlying the malignant transformation of pre-existing neurofibromas (PNST) to malignant peripheral nerve sheath tumors (MPNST) in individuals with neurofibromatosis type 1 (NF1). Our primary focus was on the role of DLK1 in this transformation process and its potential as a biomarker for diagnosis, risk assessment, and therapeutic stratification.

Population Information

This study consisted of a case set of peripheral nerve sheath tumor specimens, including plexiform neurofibromas, atypical neurofibromas, and MPNSTs, acquired under IRB approval at our institution. The majority of the subjects had neurofibromatosis type 1.

Principal Findings

  1. DLK1 Overexpression: The study found that DLK1 is significantly increased in MPNST compared to non-malignant neurofibromas.
  2. Early Marker: DLK1 overexpression may precede histological changes indicative of malignancy.
  3. Serum Levels: Higher serum levels of DLK1 were observed in both mice and humans with MPNST.
  4. Molecular Stratification: Divergent levels of DLK1 expression identified distinct MPNST subsets with unique molecular characteristics and potential therapeutic targets.
  5. Clinical Implications: Overexpression of DLK1 was associated with the reactivation of embryonic signatures, an immunosuppressive microenvironment, and poorer overall survival in NF1-MPNST patients.

Data Availability

Whole exome sequencing, bulk RNA sequencing, and single-cell RNA sequencing data from this study will be made available through the database of Genotypes and Phenotypes (dbGaP) to support further research and validation studies.