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Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas
Author(s) -
Jour George,
Andeen Nicole K,
alRohil Rami,
Aung Phyu P,
Mehrotra Meenakshi,
Duose Dzifa,
Hoch Benjamin,
Argenyi Zolt,
Luthra Rajyalakshmi,
Wistuba Ignacio I,
Prieto Victor G
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4996
Subject(s) - biology , cancer research , melanoma , gene , immune checkpoint , carcinogenesis , mutation , gene expression , cancer , genetics , immunotherapy
Abstract 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.