Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

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 FerrerTrevor J. Pugh, Kenneth D. Aldape, Laura Papi, Gelareh Zadeh

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)101-116
Number of pages16
JournalActa Neuropathologica
Volume141
Issue number1
DOIs
StatePublished - Jan 2021

Bibliographical note

Funding Information:
We would like to thank Jenna Eagles, Alberto Leon and Kayla Marsh for processing samples at the OICR. This project was supported by the Children’s Tumor Foundation through its Synodos for Schwannomatosis Consortium program (Grants 2018-18-005A to GZ, 2018-18-005C to LP, 2018-18-005D to ASR, and 2018-18-005E to KO). An additional grant supporting this project was from the Istituto Toscano Tumori and Ministero della Salute (PE-2011-02348918) awarded to LP.

Funding Information:
We would like to thank Jenna Eagles, Alberto Leon and Kayla Marsh for processing samples at the OICR. This project was supported by the Children?s Tumor Foundation through its Synodos for Schwannomatosis Consortium program (Grants 2018-18-005A to GZ, 2018-18-005C to LP, 2018-18-005D to ASR, and?2018-18-005E to KO). An additional grant supporting this project was from the Istituto Toscano Tumori and Ministero della Salute (PE-2011-02348918) awarded to LP.

Publisher Copyright:
© 2020, The Author(s).

Keywords

  • Genomics
  • LZTR1
  • MAPK
  • Pain
  • Peripheral nerve sheath tumors
  • Schwannomatosis

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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