Unmasking Intra-Tumoral Heterogeneity and Clonal Evolution in NF1-MPNST

Abstract

Sarcomas are highly aggressive cancers that have a high propensity for metastasis, fail to respond to conventional therapies, and carry a poor 5-year survival rate. This is particularly true for patients with neurofibromatosis type 1 (NF1), in which 8%–13% of affected individuals will develop a malignant peripheral nerve sheath tumor (MPNST). Despite continued research, no effective therapies have emerged from recent clinical trials based on preclinical work. One explanation for these failures could be the lack of attention to intra-tumoral heterogeneity. Prior studies have relied on a single sample from these tumors, which may not be representative of all subclones present within the tumor. In the current study, samples were taken from three distinct areas within a single tumor from a patient with an NF1-MPNST. Whole exome sequencing, RNA sequencing, and copy number analysis were performed on each sample. A blood sample was obtained as a germline DNA control. Distinct mutational signatures were identified in different areas of the tumor as well as significant differences in gene expression among the spatially distinct areas, leading to an understanding of the clonal evolution within this patient. These data suggest that multi-regional sampling may be important for driver gene identification and biomarker development in the future.

Special Issue: “Genomics and Models of Nerve Sheath Tumors”

“…Moon and Tompkins et al performed a comprehensive genomic analysis of multiple areas from within a single large MPNST. These authors identify varied genomic profiles within each area, highlighting the need for further studies on intra-tumoral heterogeneity in order to truly understand the genomic composition of any given tumor [ 5 ]. Such studies are critical to aid in our understanding of tumor and patient responsiveness and non-responsiveness to a range of therapies.…”

Enhancer reprogramming in PRC2-deficient malignant peripheral nerve sheath tumors induces a targetable de-differentiated state

“…Other studies have identified an increase in histone posttranslational modifications like H3K27Ac and H3K36me3 along with a global increase in DNA methylation levels in MPNST [84], but the chromatin regions undergoing this epigenetic reordering are reported for the first time in our study. A recent study has shown spatial heterogeneity of MPNST tumors by sampling multiple sites of same tumor [55]. Bulk sequencing approaches used in our study cannot identify this cellular heterogeneity and presents as a study limitation.…”

p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs

“…Resistant clonal populations within heterogeneous MPNSTs may explain the clinical failures of targeted kinase inhibitors in MPNSTs [ 44 ]. To determine if p53 is a key driver of clonal selection and drug resistance in MPNSTs, we performed a clonal competition assay using labeled isogenic NF1-MET-GFP and NF1-MET;sgP53-RFP cell lines.…”