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

Publication ,  Journal Article
Jour, G; Andeen, NK; Al-Rohil, R; Aung, PP; Mehrotra, M; Duose, D; Hoch, B; Argenyi, Z; Luthra, R; Wistuba, II; Prieto, VG
Published in: J Pathol
January 2018

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. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Published In

J Pathol

DOI

EISSN

1096-9896

Publication Date

January 2018

Volume

244

Issue

1

Start / End Page

97 / 106

Location

England

Related Subject Headings

  • Tumor Microenvironment
  • Sequence Analysis, RNA
  • Sequence Analysis, DNA
  • Pathology
  • Neurilemmoma
  • Mutation
  • Middle Aged
  • Melanoma
  • Male
  • Humans
 

Citation

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Jour, G., Andeen, N. K., Al-Rohil, R., Aung, P. P., Mehrotra, M., Duose, D., … Prieto, V. G. (2018). Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas. J Pathol, 244(1), 97–106. https://doi.org/10.1002/path.4996
Jour, George, Nicole K. Andeen, Rami Al-Rohil, Phyu P. Aung, Meenakshi Mehrotra, Dzifa Duose, Benjamin Hoch, et al. “Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas.J Pathol 244, no. 1 (January 2018): 97–106. https://doi.org/10.1002/path.4996.
Jour G, Andeen NK, Al-Rohil R, Aung PP, Mehrotra M, Duose D, et al. Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas. J Pathol. 2018 Jan;244(1):97–106.
Jour, George, et al. “Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas.J Pathol, vol. 244, no. 1, Jan. 2018, pp. 97–106. Pubmed, doi:10.1002/path.4996.
Jour G, Andeen NK, Al-Rohil R, Aung PP, Mehrotra M, Duose D, Hoch B, Argenyi Z, Luthra R, Wistuba II, Prieto VG. Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas. J Pathol. 2018 Jan;244(1):97–106.
Journal cover image

Published In

J Pathol

DOI

EISSN

1096-9896

Publication Date

January 2018

Volume

244

Issue

1

Start / End Page

97 / 106

Location

England

Related Subject Headings

  • Tumor Microenvironment
  • Sequence Analysis, RNA
  • Sequence Analysis, DNA
  • Pathology
  • Neurilemmoma
  • Mutation
  • Middle Aged
  • Melanoma
  • Male
  • Humans