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Open Access 01-01-2021 | Schwannoma | Original Paper

Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Authors: Sheila Mansouri, Suganth Suppiah, Yasin Mamatjan, Irene Paganini, Jeffrey C. Liu, Shirin Karimi, Vikas Patil, Farshad Nassiri, Olivia Singh, Yogi Sundaravadanam, Prisni Rath, Roberta Sestini, Francesca Gensini, Sameer Agnihotri, Jaishri Blakeley, Kimberly Ostrow, David Largaespada, Scott R. Plotkin, Anat Stemmer-Rachamimov, Marcela Maria Ferrer, Trevor J. Pugh, Kenneth D. Aldape, Laura Papi, Gelareh Zadeh

Published in: Acta Neuropathologica | Issue 1/2021

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.

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Title: Epigenomic, genomic, and transcriptomic landscape of schwannomatosis
Authors: Sheila Mansouri
Suganth Suppiah
Yasin Mamatjan
Irene Paganini
Jeffrey C. Liu
Shirin Karimi
Vikas Patil
Farshad Nassiri
Olivia Singh
Yogi Sundaravadanam
Prisni Rath
Roberta Sestini
Francesca Gensini
Sameer Agnihotri
Jaishri Blakeley
Kimberly Ostrow
David Largaespada
Scott R. Plotkin
Anat Stemmer-Rachamimov
Marcela Maria Ferrer
Trevor J. Pugh
Kenneth D. Aldape
Laura Papi
Gelareh Zadeh
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keyword: Schwannoma
Published in: Acta Neuropathologica / Issue 1/2021
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-020-02230-x

At a glance: The STEP trials

Springer Medicine

Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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