Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas.
George JourNicole K AndeenRami Al-RohilPhyu P AungMeenakshi MehrotraDzifa DuoseBenjamin HochZolt ArgenyiRajyalakshmi LuthraIgnacio I WistubaVictor G PrietoPublished in: The Journal of pathology (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.
Keyphrases
- copy number
- gene expression
- peripheral nerve
- nuclear factor
- genome wide
- dna methylation
- mitochondrial dna
- genome wide identification
- signaling pathway
- circulating tumor
- single molecule
- clinical trial
- nucleic acid
- toll like receptor
- single cell
- high throughput
- cell free
- pi k akt
- lps induced
- transcription factor
- end stage renal disease
- soft tissue
- cell proliferation
- newly diagnosed
- small cell lung cancer
- cancer therapy
- vascular endothelial growth factor
- inflammatory response
- papillary thyroid
- ejection fraction
- endothelial cells
- chronic kidney disease
- immune response
- oxidative stress
- tyrosine kinase
- genome wide analysis
- epidermal growth factor receptor
- rheumatoid arthritis
- low grade
- squamous cell carcinoma
- patient reported outcomes
- wound healing
- binding protein
- cell migration