American Society for Peripheral Nerve
ASPN Home ASPN Home Past & Future Meetings Past & Future Meetings

Back to 2023 Abstracts


Comprehensive Genomic and Epigenomic Characterization of the Spectrum of Peripheral Nerve Sheath Tumors Associated With NF1 Identifies Two Distinct MPNST Subtypes
Suganth Suppiah, MD, PhD1; Sheila Mansouri, PhD1; Yasin Mamatjan, PhD1; Jeff Liu, PhD1; Vikas Patel, PhD1; Gelareh Zadeh, MD, PhD2
1University of Toronto, Toronto, ON, Canada; 2University of Toront, Toronto, ON, Canada

Introduction: Neurofibromatosis type 1 (NF-1) is a tumor predisposition syndrome that results in the development of innumerable peripheral nerve sheath tumors. These tumors fall within a spectrum of benign, premalignant and malignant tumors. Here, we provide an integrated molecular characterization of the spectrum of peripheral nerve sheath tumors and identify two novel molecular subtypes of MPNSTs that are driven by SHH or WNT pathway activation.
Methods: We investigated the DNA methylation patterns of a spectrum of peripheral nerve sheath tumors (N=108). The methylation classes were further characterized by WES and RNA sequencing on a subset of tumors. In addition, functional validation of identified pathways was performed using CRISPR/cas9 knockout in immortalized neurofibroma cell lines.
Results: Unsupervised consensus hierarchical clustering yielded seven stable and robust subgroups that are clinically relevant. The high-grade MPNSTs formed two distinct methylation-based clusters (MPNST-G1 and MPNST-G2). PTCH1 loss was prevalent in MPNST-G1 compared to MPNST-G2 (75% vs 12.5%, p < 0.05). Transcriptome profiling recapitulated the two distinct MPNST subgroups. Gene set enrichment analysis (GSEA) demonstrated that RB1 and PRC2 signaling pathways are aberrant in both MPNST-G1 and MPNST-G2. However, SHH pathway activation is observed in MPNST-G1, while WNT and CCND1 pathway activation is observed in MPNST-G2. To determine if SHH pathway activation is sufficient for malignant transformation, we knocked out PTCH1in immortalized neurofibroma cells lines and observed induction of a malignant phenotype, with increased cellular proliferation and invasion.
Conclusions: Our integrative genomics approach to a large cohort of the spectrum of peripheral nerve sheath tumors identified two novel MPNST subgroups. The MPNST subgroups can be reliably assigned to subgroups through methylome and transcriptome signatures. Future research on MPNSTs and the development of clinical trials should take into consideration these two distinct types of MPNSTs to target these pathways as a novel therapeutic approach


Back to 2023 Abstracts