5 years ago

Novel enriched pathways in superficial malignant peripheral nerve sheath tumors (MPNST) and spindle/desmoplastic melanomas (SDM)

Rami al -Rohil, Dzifa Duose, George Jour, Rajyalakshmi Luthra, Nicole K Andeen, Ignacio I Wistuba, Benjamin Hoch, Meenakshi Mehrotra, Zolt Argenyi, Phyu P Aung, Victor G Prieto
Superficial malignant peripheral nerve sheath tumor (MPNST) is a rare, soft tissue neoplasm that shares morphological features and some molecular events with spindle and desmoplastic melanoma (SDM). Herein we sought to identify molecular targets for therapy using targeted RNA/DNA sequencing and gene expression of key immunological players. DNA and RNA from formalin-fixed, paraffin-embedded (FFPE) tissue were extracted and processed. Massive high-throughput deep parallel sequencing was performed using the Oncomine comprehensive panel enabling detection of relevant SNVs, CNVs, gene fusions, and indels from 143 unique genes on the Ion torrent sequencer for clinical trial research programs. Gene expression analysis was carried out using a customized 770 gene expression panel combining markers for 24 different immune cell types and 30 common cancer antigens including key checkpoint blockade genes analyzed using 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 MPNST and 67% of SDM with 50% of the mutations involving the RAS binding domain. Inactivating/deleterious mutations of TSC1/TSC2 were identified in 40% and 41% of MPNST and SDM cases, respectively. Activating mutations affecting the EGFR-like and the negative regulatory domains of NOTCH1and KDR (VEGFR2) mutations were identified in 45% and 40% of SDM and 30% and 8% MPNST cases, respectively. Differential gene expression and gene clustering analysis showed significantly perturbed immune pathway components including NF-κB, JAK/STAT, CXCL12/CXCR4 and differentially expressed CD274 and CTLA4 in both SDM and MPNST. Angiogenesis (KDR and NOTCH1) and mTORC pathways offer a rationale for anti-angiogenic and selective mTORC inhibition as treatment strategies for MPNST and SDM. Cytokines, JAK/STAT, TNF and NF-κB axes were perturbed in both SDM and MPNST. These pathways have been targeted in hematological malignancies and present promising targets for these tumors.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/path.4996

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