A clinically and genomically annotated nerve sheath tumor biospecimen repository

Pollard, Kai; Banerjee, Jineta; Doan, Xengie; Wang, Jiawan; Guo, Xindi; Allaway, Robert J.; Langmead, Shannon; Slobogean, Bronwyn; Meyer, Christian F.; Loeb, David M.; Morris, Carol D.; Belzberg, Allan J.; Blakeley, Jaishri O.; Rodríguez, Fausto J.; Guinney, Justin; Gosline, Sara J.C.; Pratilas, Christine A.

doi:10.1038/s41597-020-0508-5

Cited by 20 publications

(18 citation statements)

References 27 publications

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“…Chr8q gain was not observed in any of the PN examined ( Figure 2B ). We also found a high degree of aneuploidy in NF1-MPNST, whereas the PN samples harbored diploid genomes, as expected based on prior publications ( 20 – 22 ).…”

Section: Resultssupporting

confidence: 89%

Chromosome 8 gain is associated with high-grade transformation in MPNST

Dehner¹,

Moon²,

Xi-yuan³

et al. 2021

JCI Insight

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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.

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Section: Resultssupporting

confidence: 89%

Chromosome 8 gain is associated with high-grade transformation in MPNST

Dehner¹,

Moon²,

Xi-yuan³

et al. 2021

JCI Insight

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“…These humanized models represent a unique opportunity to study the characteristics of a large variety of tumor types, as early passage PDX lines retain a high degree of similarity to the parental tumor and allow study of tumor cell origin, biomarker identification, and treatment strategies (17-19). We generated and characterized eight NF1-MPNST PDX from eight corresponding biopsy-proven human NF1-MPNST between 2014 and 2019 at two institutions, Washington University and John Hopkins University (20). These lines represent the largest characterized set of NF1-MPNST PDX reported to date.…”

Section: Resultsmentioning

confidence: 99%

Chromosome 8 gain is associated with high-grade transformation in MPNST

Dehner

Moon

Zhou

et al. 2020

Preprint

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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 which 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 success 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 to the primary tumors from which they were derived using copy number analysis, whole exome 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. Taken together, 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.

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“…In order to confirm whether CNFs and PNFs are genomically and transcriptomically distinct lesions using advanced sequencing techniques, we compared publicly available RNA-seq data from an NF1 test cohort where cutaneous/non-plexiform neurofibromas were compared to PNFs [ 16 ]. Principal Component Analysis (PCA) of the RNA-seq data confirmed that histologically similar cutaneous CNFs and PNFs cannot be discriminated based on global gene expression profiles, largely due to transcript heterogeneity (Fig.…”

Section: Resultsmentioning

confidence: 99%

Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling

Grit

Johnson

Dischinger

et al. 2021

Epigenetics & Chromatin

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Benign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

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A clinically and genomically annotated nerve sheath tumor biospecimen repository

Cited by 20 publications

References 27 publications

Chromosome 8 gain is associated with high-grade transformation in MPNST

Chromosome 8 gain is associated with high-grade transformation in MPNST

Chromosome 8 gain is associated with high-grade transformation in MPNST

Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling

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