Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways that Define Tumor Heterogeneity in NF1

Abstract

Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40–60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions.

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 , 45 ]. Additionally, we observed broader copy number gains in chromosome arms 1q, 7p, 8q, 9q, and 17q as well as broad losses in arms 6p and 9p only in MPNST patient plasma, again consistent with previous findings from NF1 MPNST tumors [ 32 , 42 , 46 ] ( Fig 3 ). 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, only within MPNST and PN patients, but not in healthy donor controls.…”

“…Previous tissue-based studies have shown that PN harbor few genome-wide CNAs [ 40 , 41 ] but acquire significant genomic instability during malignant transformation to MPNST [ 32 , 41 , 42 ]. Based on these known significant CNA differences between MPNST and PN tumors, we assumed a large effect size would also be evident comparing MPNST plasma tumor fraction to plasma from PN patients or healthy controls.…”

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 [32,45]. Additionally, we observed broader copy number gains in chromosome arms 1q, 7p, 8q, 9q and 17q as well as broad losses in arms 6p and 9p only in MPNST patient plasma, again consistent with previous findings from NF1 MPNST tumors [32,42,46] (Figure 3). 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, only within MPNST and PN patients, but not in healthy donor controls.…”

“…Previous tissue-based studies have shown that PN harbor few genome-wide CNAs [40,41] but acquire significant genomic instability during malignant transformation to MPNST [32,41,42]. Based on these known significant CNA differences between MPNST and PN tumors, we assumed a large effect size would also be evident comparing MPNST plasma tumor fraction to plasma from PN patients or healthy controls.…”

The quest for effective immunotherapies against malignant peripheral nerve sheath tumors: Is there hope?

“…Bioinformatic deconvolution algorithms from gene expression studies have predicted the microenvironment of MPNSTs to contain activated mast cells, protumor M2-like macrophages, resting CD4+ memory T cells, and cancer-associated fibroblasts. 9 We discuss some recent findings that have been pivotal in shaping our understanding of immune infiltrates in MPNSTs below.…”