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.
Highlights
Schwannomatosis (SWNTS; MIM #162091) is a genetic cancer-predisposing syndrome and a form of neurofibromatosis (NF) that affects approximately 1 in 126,315 individuals [11] and is characterized by the development of multiple non-intradermal schwannomas (SWNs), mainly in the peripheral nerves (90%) and spinal nerves (75%), and, less commonly, cranial nerves [30]
Venn diagram to the right shows the number of variants called by both WES and WGS. c Plots showing compounded arm-level CNV in SWNTS-SWNs versus non-syndromic SWNs (NS-SWNs). d GISTIC plots showing significant focal deletions in SWNTS-SWNs and NS-SWNs methylation signatures, coding mutations, copy number variations (CNVs), structural variations (SVs), transcriptional profile, and the presence of gene fusions
We evaluated the proportion of different immune cells infiltrating SWNs using our RNAseq and demonstrated that SWNTSSWNs displayed a statistically higher proportion of naïve B cells, plasma cells, and activated natural killer (NK) cells, but lower number of total macrophages and CD8+ T cells compared to NS-SWNs (Student’s t test, p < 0.05, Fig. 5a–g)
Summary
Schwannomatosis (SWNTS; MIM #162091) is a genetic cancer-predisposing syndrome and a form of neurofibromatosis (NF) that affects approximately 1 in 126,315 individuals [11] and is characterized by the development of multiple non-intradermal schwannomas (SWNs), mainly in the peripheral nerves (90%) and spinal nerves (75%), and, less commonly, cranial nerves [30]. While the majority of SWNTS in the general population occur sporadically, 13–25% are associated with the autosomal dominant tumor suppressor SWNTS or NF3 syndrome with reduced penetrance [3, 28, 30]. While SWNs that occur in SWNTS are phenotypically and histopathologically indistinguishable from those that develop in NF2 disease and the non-syndromic SWNs (NS-SWNs), early evidence indicates that the molecular pathways and drivers of these tumors are very different. The molecular drivers of tumor formation in a large proportion of SWNTS-SWNs remain unknown
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