Integrated Multi-Omics Characterization of Neurofibromatosis Type 1 Related Peripheral Nerve Sheath Tumors Identifies Two Distinct Malignant Peripheral Nerve Sheath Tumors Subtypes with Sonic Hedgehog or WNT Pathway Activation. (1st September 2019)

• Record Type: Journal Article
• Authors: Suppiah, Suganth; Liu, Jeff; Wei, Qingxia; Mamatjan, Yasin; Heir, Pardeep; Nassiri, Farshad; Mansouri, Sheila; Aldape, Kenneth; Zadeh, Gelareh
• Is Part Of: Neurosurgery. Volume 66(2010)Supplement 1
• Publication Date: 2019-09-01
• Subjects: Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1093/neuros/nyz310_138
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract: INTRODUCTION: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann-cell derived sarcomas and the leading cause of mortality in neurofibromatosis Type 1. In many cases, MPNSTs develop through malignant transformation of an underlying neurofibroma (NF). The genomic alterations and molecular pathways driving malignant transformation is not well understood. In this study, we leverage multi-platform genomic and epigenomic profiling of human NFs and MPNSTs to identify targetable molecular pathways that lead to malignant transformation. METHODS: Fresh-frozen tumor (N = 108; 19 MPNSTs, 18 premalignant NFs, 37 benign peripheral nerve NFs, and 34 cutaneous NFs) and matched-controls were allocated for NGS platforms including methylation-profiling, RNA, whole exome and ChIP sequencing. In addition, functional validation of identified pathways was performed using CRISPR/cas9 knockout of relevant sonic hedgehog (SHH) and WNT pathway genes in immortalized neurofibroma cell lines. RESULTS: Unsupervised consensus clustering of peripheral nerve tumors identified 4 distinct methylation subgroups, with MPNSTs clustering in either Methyl_Grp-2B or Methyl_Grp-3. Transcriptomic analysis of the MPNSTs, identified SHH pathway activation in Methyl_Grp-3 MPNSTs (NES = 1.9952, P < .0001, FDR < 0.001) and WNT pathway activation in Methyl_Grp-2B MPNSTs (NES = 1.7630, P < .0001, FDR = 0.0058). Single sample gene set enrichment analysis demonstrates that there is a strong negative correlation between SHH and WNT pathway activation in MPNSTs (r = −0.78, P = .007). Methyl_Gr-3 MPNSTs harbor more PTCH1 copy number loss (62.5% vs 0%, P < .05) and PTCH1 promoter hypermethylation (mean beta value: 0.2899 vs. 0.06119, P < .05). PTCH1 knockout in immortalized neurofibroma cell lines increased expression of SHH pathway target genes (GLI1, GLI2, and SMO), and increased cellular proliferation and invasiveness. CONCLUSION: We found that MPNSTs can be classified into two molecular subgroups driven by SHH or WNT pathway activation. Furthermore, PTCH1 loss is one mechanism that mediates SHH pathway activation. These results suggest a targeted approach should be taken for treating MPNSTs, and SHH and WNT pathway inhibition may be promising avenue for therapeutic development.