Establishment and genomic characterization of a sporadic malignant peripheral nerve sheath tumor cell line

Jody Fromm Longo,Iya Znoyko,Dorea P Jenkins,Stephanie N Brosius,Steven L Carroll,Daynna J Wolff,Robert C Wilson,Victoria A Alers,Kevin A Roth,Andrew J Carroll

doi:10.1038/s41598-021-85055-2

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived neoplasms that occur sporadically or in patients with neurofibromatosis type 1 (NF1). Preclinical research on sporadic MPNSTs has been limited as few cell lines exist. We generated and characterized a new sporadic MPNST cell line, 2XSB, which shares the molecular and genomic features of the parent tumor. These cells have a highly complex karyotype with extensive chromothripsis. 2XSB cells show robust invasive 3-dimensional and clonogenic culture capability and form solid tumors when xenografted into immunodeficient mice. High-density single nucleotide polymorphism array and whole exome sequencing analyses indicate that, unlike NF1-associated MPNSTs, 2XSB cells have intact, functional NF1 alleles with no evidence of mutations in genes encoding components of Polycomb Repressor Complex 2. However, mutations in other genes implicated in MPNST pathogenesis were identified in 2XSB cells including homozygous deletion of CDKN2A and mutations in TP53 and PTEN. We also identified mutations in genes not previously associated with MPNSTs but associated with the pathogenesis of other human cancers. These include DNMT1, NUMA1, NTRK1, PDE11A, CSMD3, LRP5 and ACTL9. This sporadic MPNST-derived cell line provides a useful tool for investigating the biology and potential treatment regimens for sporadic MPNSTs.

Highlights

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived neoplasms that occur sporadically or in patients with neurofibromatosis type 1 (NF1)
To assess the possibility that this neoplasm might be a monophasic synovial sarcoma, we sequenced the transcriptome of the tumor and examined it for fusion genes using multiple algorithms (deFuse[21], Tophat-Fusion[8] and STAR-Fusion22)
The patient from which the tumor was resected had no previous diagnosis of any malignancy, lacked the clinical features characteristic of NF1 and had no previous history of radiotherapy, leading us to conclude that this tumor was a sporadic MPNST

Summary

Introduction

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived neoplasms that occur sporadically or in patients with neurofibromatosis type 1 (NF1). This is because comprehensive genomic analyses have been performed on only a very small number of these neoplasms Those studies that are available indicate that while some sporadic MPNSTs have NF1 loss and mutations of genes encoding PRC2 c omponents[18,19], these mutations are not uniformly present in sporadic MPNSTs. The natural history of sporadic MPNSTs is distinct—sporadic MPNSTs typically arise de novo rather than from a pre-existing plexiform neurofibroma, and they occur in patients 25–30 years older than patients with NF1-associated MPNSTs. Defining the genomic abnormalities in sporadic MPNSTs is essential if we are to understand the pathogenesis of these tumors and develop new therapies that are effective against them.

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Results

Conclusion