Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Abstract

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.

Massive vagal schwannoma in an 11‐year‐old girl

“…TET1 plays a role in epigenetic tumorigenesis and may be implicated in schwannomatosis. 5 The clinicopathologic significance of the alteration in the setting of pediatric vagal schwannoma is unclear.…”

Neurofibromatosis: Molecular Pathogenesis and Natural Compounds as Potential Treatments

“…Schwannomatosis manifests as multiple schwannomas on nerves throughout the body but without involvement of vestibular nerves (1,25). The true incidence of schwannomatosis is unknown but thought to be similar to NF2.…”

“…Cul3-containing ubiquitin ligases promote cell differentiation, and LZTR1-depleted Schwann cells have gene expression signatures consistent with a demyelinated proliferative phenotype. Additionally, recent evidence indicates that LZTR1-mutant schwannomatosis schwannomas exhibit deregulated VEGF receptor, ErbB3, and ERK signaling (25). SMARCB1 is a component of the SWI/SNF chromatin remodeling complex, which affects the accessibility of genes to transcription factors and RNA polymerases (50).…”

“…It should be emphasized that although NF1-, NF2-, and schwannomatosis-related tumors have distinct genetic origins, they share downstream activation of several molecular targets (1,2,6,16,25,52). Collectively, these deregulated signaling pathways due to tumor suppressor loss in NF-associated tumors provide several targets for therapeutic development.…”

LZTR1: A promising adaptor of the CUL3 family (Review)

“…However, unlike other BTB-Kelch proteins, LZTR1 shows no interaction with actin but is localized on the Golgi complex ( 40 ), suggesting a unique function and status. Mutations in the LZTR1 gene occur in ≤8% of patients with NS ( 46 , 47 ), 4.4% of those with GBM ( 39 , 48 ) and 24.4% of those with schwannomatosis ( Table I ) ( 49 – 51 ). The occurrence of these diseases is related to abnormal function of RAS proteins, demonstrating a close relationship between LZTR1 and proteins of the RAS superfamily ( 38 , 52 – 54 ).…”