Epigenomic, genomic, and transcriptomic landscape of schwannomatosis
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ORIGINAL PAPER
Epigenomic, genomic, and transcriptomic landscape of schwannomatosis Sheila Mansouri1 · Suganth Suppiah1 · Yasin Mamatjan1 · Irene Paganini2 · Jeffrey C. Liu1 · Shirin Karimi1 · Vikas Patil1 · Farshad Nassiri1 · Olivia Singh1 · Yogi Sundaravadanam3 · Prisni Rath3 · Roberta Sestini2 · Francesca Gensini2 · Sameer Agnihotri4 · Jaishri Blakeley5 · Kimberly Ostrow5 · David Largaespada6 · Scott R. Plotkin7 · Anat Stemmer‑Rachamimov7 · Marcela Maria Ferrer8 · Trevor J. Pugh3 · Kenneth D. Aldape9 · Laura Papi2 · Gelareh Zadeh1,10,11 Received: 31 July 2020 / Revised: 23 September 2020 / Accepted: 23 September 2020 © The Author(s) 2020
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. Keywords Schwannomatosis · Peripheral nerve sheath tumors · LZTR1 · Genomics · Pain · MAPK Sheila Mansouri, Suganth Suppiah, Yasin Mamatjan and Irene Paganini contributed equally to the manuscript. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-020-02230-x) contains supplementary material, which is available to authorized users. * Gelareh Zadeh [email protected] 1
Princess Margaret Cancer Center and MacFeeters‑Hamilton Center for Neuro‑Oncology Research, University Health Network, Wilkins Family Chair in Brain Tumor Research, 14‑701 PMCRT, 101 College St, Toronto, ON M5G 1L7, Canada
2
The Department of Experimental and Clinical, Medical Genetics Unit, Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
3
Ontario Institute for Cancer Research, Toronto, ON, Canada
4
Department of Neurological Surgery, Children’s Hospital, University of Pittsburgh, Pittsburgh, PA, USA
5
Johns Hopkins University, Baltimore, MD, USA
6
Department of Paediatrics, University of MN, Minneapolis, USA
7
Department of Pathology, Massachuse
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