Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas

George Jour, Nicole K. Andeen, Rami al-Rohil, Phyu P. Aung, Meenakshi Mehrotra, Dzifa Duose, Benjamin Hoch, Zolt Argenyi, Rajyalakshmi Luthra, Ignacio I. Wistuba, Victor G. Prieto

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Superficial malignant peripheral nerve sheath tumour (MPNST) is a rare, soft tissue neoplasm that shares morphological features and some molecular events with spindle/desmoplastic melanoma (SDM). Herein, we sought to identify molecular targets for therapy by using targeted RNA/DNA sequencing and gene expression of key immunological players. DNA and RNA from formalin-fixed paraffin-embedded tissue were extracted and processed. Massive high-throughput deep parallel sequencing was performed with the Oncomine comprehensive panel, enabling detection of relevant single-nucleotide variants, copy number variations, gene fusions and indels for 143 unique genes on the Ion torrent sequencer for clinical trial research programmes. Gene expression analysis was carried out with a customized 770-gene expression panel combining markers for 24 different immune cell types and 30 common cancer antigens, including key checkpoint blockade genes analysed with the Ncounter system. Fifty-one patients (SDM, 16/11; MPNST, 24; male, n = 37; female, n = 16) had sufficient DNA and RNA for testing. NF1 deleterious mutations and/or deep/homozygous deletions were identified in 73% of MPNSTs and 67% of SDMs, with 50% of the mutations involving the RAS-binding domain. Inactivating/deleterious mutations of TSC1/TSC2 were identified in 40% and 41% of MPNSTs and SDMs, respectively. Activating mutations affecting the EGFR-like and the negative regulatory domains of NOTCH1 and KDR (VEGFR2) were identified in 45% and 40% of SDMs and in 30% and 8% of MPNSTs, respectively. Differential gene expression and gene clustering analysis showed significantly perturbed immune pathway components, including nuclear factor-κB (NF-κB), JAK–STAT, and CXCL12–CXCR4, and differentially expressed CD274 and CTLA4, in both SDM and MPNST. Angiogenesis (KDR and NOTCH1) and mammalian target of rapamycin complex (mTORC) pathways offer a rationale for anti-angiogenic and selective mTORC inhibition as treatment strategies for MPNST and SDM. Cytokines and the JAK–STAT, TNF and NF-κB axes were perturbed in both SDM and MPNST. These pathways have been targeted in haematological malignancies and present promising targets for these tumours.

Original languageEnglish (US)
Pages (from-to)97-106
Number of pages10
JournalJournal of Pathology
Issue number1
StatePublished - Jan 2018
Externally publishedYes


  • gene expression
  • immune blockade
  • spindle cell melanoma, desmoplastic melanoma
  • superficial malignant peripheral nerve sheath tumour
  • targeted RNA/DNA sequencing

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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