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

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 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.

Cell-free DNA ultra-low-pass whole genome sequencing to distinguish malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion: a cross-sectional study

“…Loss of SUZ12 correlated with NF1 loss, consistent with both genes' location in the 17.q11.2 genomic locus [32,42]. Additionally, we observed broader copy number gains in chromosome arm 8q and broad losses in arm 9p only in plasma from an MPNST patient, again consistent with previous findings from NF1 patient tumors [32,40,43] (Figure 2). Finally, while many types of NF1 gene activation can underlie the NF1 disease process, we observed evidence of one of these, NF1 copy number loss, within our cohort only among MPNST and PN patients, but not in healthy donor controls.…”