Abstract
One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy number analysis, whole exome sequencing, and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single-cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft-tissue sarcomas. These data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis and may account for the aggressive nature and poor outcomes in this sarcoma subtype.
Highlights
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas with a devastating prognosis
Numerous in vivo tumor models have been developed for preclinical studies, but there is limited genetic diversity modeled in these systems, and they do not capture the full spectrum of genetic heterogeneity found in human NF1MPNST
Correlation of the variant allele frequency (VAF) in the parental tumor versus the VAF in each patient-derived xenografts (PDX) demonstrated similarity of the PDX compared with its parental tumor
Summary
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas with a devastating prognosis. About half of MPNST arise in patients with an underlying autosomal dominant genetic disorder, Neurofibromatosis type 1 (NF1), while the other half arise de novo or in the setting of prior radiation therapy [1,2,3]. Mutations in other genes such as TP53, EED, SUZ12, and CDKN2A are required for malignant transformation to MPNST [8, 9]. Despite advances in understanding the oncogenic drivers of MPNST, chemotherapy is inconsistently beneficial, and other effective therapies are lacking. TP53 loss, for example, is a common feature of the currently used preclinical models, but it is observed only in a minority of human MPNST [14, 15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
