The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

Abstract

Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cellederived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1eassociated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16 INK4A -cyclin D1-CDK4-Rb and p19 ARF -Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis. (Am J Pathol 2016, 186: 464e477; http://dx

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

“…Neurofibromatosis is a syndrome with Schwann cell-derived tumors caused by loss of either the NF1 or NF2 tumor suppressors (Carroll 2016). Loss of NF1 is associated with an increased risk that the disease progresses from benign neurofibromas to malignant peripheral nerve sheath tumors (MPNST’s).…”

Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1

“…Nf1 −/− E1A-p53 MEFs were created by transforming MEFs harboring a germline bi-allelic inactivating Nf1 mutation, with an E1A oncogene and dominant-negative p53 (8). Such transformation partially recapitulates p53 and Rb inactivation that are often seen in NF1-associated malignancies (9, 10). …”

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

“…22, 23, and Figure 2B). In addition, key signaling pathways in MPNSTs, including the Wnt/β-catenin, PI3K/AKT/mTOR, and RAS pathways (1,2), were also enriched ( Figure 2, B-D, and Supplemental Table 3).…”

“…HuR regulates key cell cycle genes in MPNSTs via an RB/E2F axis. RAS/MEK/ERK and PI3K/AKT/mTOR are 2 other major signaling pathways that are upregulated in MPNSTs and have important roles in MPNST pathogenesis (1,2). GSEA analysis revealed that many components of these pathways were significantly downregulated by HuR silencing, including activation of receptor tyrosine kinases such as PDGF (Supplemental Figure 9, A and B).…”

“…HuR is frequently upregulated in different A number of mutations that drive MPNST pathogenesis have been identified, with a surprising degree of overlap in NF1-associated and sporadic forms. These include molecular variants of the NF1 tumor suppressor gene that are present in all NF1 patients, and in a majority of sporadic and radiation-induced MPNSTs (2,3). Other ancillary, yet essential, cancer-driving genetic aberrations include loss of the genes CDKN2A, TP53, RB, or PTEN, or the genes encoding the PRC2 components SUZ12 or EED, and amplification of PDGFRA, EGFR, or MET (4,5).…”