Malignant Peripheral Nerve Sheath Tumor — MSKCC

Overview

Multi-platform genomic characterization of malignant peripheral nerve sheath tumors (MPNSTs) generated at Memorial Sloan Kettering Cancer Center by Lee et al. (2014). The discovery cohort used whole-exome sequencing, SNP6.0 copy number arrays, and RNA-seq on 15 fresh-frozen tumor/normal pairs from 12 patients. A validation cohort of 37 FFPE MPNSTs and 7 neurofibromas from 32 NF1 patients was profiled by MSK-IMPACT targeted hybrid-capture sequencing.

Composition

  • Cancer type: MPNST (malignant peripheral nerve sheath tumor).
  • Discovery cohort: 15 fresh-frozen MPNSTs from 12 patients — 6 NF1-associated, 4 sporadic, 4 radiotherapy-associated, 1 epithelioid.
  • Validation cohort: 37 FFPE MPNSTs and 7 neurofibromas from 32 NF1 patients.
  • Functional validation: ST88-14 (NF1-associated, SUZ12-deficient) and MPNST724 (PRC2-wt) cell lines.

Assays / panels (linked)

  • whole-exome-seq — Illumina HiSeq-2500, paired-end 51 bp; aligned to hg19 with STAR v2.3; MuTect, Strelka, VarScan variant calling.
  • rna-seq — TruSeq, Illumina HiSeq-2500, ~68M paired-end reads/sample; STAR alignment.
  • affymetrix-snp6 — Affymetrix SNP6.0 arrays for copy-number profiling.
  • msk-impact-panel — targeted hybrid-capture (includes NF1, SUZ12, EED, CDKN2A, TP53) on validation cohort.

Papers using this cohort

  • PMID:25240281 — Lee et al. (2014), Nature Genetics. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors.

Notable findings derived from this cohort

  • Loss-of-function alterations in EED or SUZ12 (PRC2 core components) are found in 92% of sporadic, 70% of NF1-associated, and 90% of radiotherapy-associated MPNSTs; EED and SUZ12 alterations are mutually exclusive PMID:25240281.
  • NF1, CDKN2A, and PRC2 (EED or SUZ12) alterations significantly co-occur (Fleiss’ κ=0.21, P=0.001) PMID:25240281.
  • PRC2 loss produces aberrant re-expression of developmentally suppressed homeobox master regulators (FOXN4, IGF2, PAX2, TLX1) and is detectable by H3K27me3 IHC loss in tumor cells PMID:25240281.
  • H3K27me3 IHC is retained in all 7 neurofibromas and lost at MPNST/neurofibroma interfaces, proposing a biomarker for malignant transformation PMID:25240281.
  • Epithelioid MPNST harbors no PRC2, NF1, or CDKN2A alterations, suggesting it is a molecularly distinct entity PMID:25240281.

Sources

  • cBioPortal study: mpnst_mskcc.

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