TY - JOUR
T1 - Epigenomic, genomic, and transcriptomic landscape of schwannomatosis
AU - Mansouri, Sheila
AU - Suppiah, Suganth
AU - Mamatjan, Yasin
AU - Paganini, Irene
AU - Liu, Jeffrey C.
AU - Karimi, Shirin
AU - Patil, Vikas
AU - Nassiri, Farshad
AU - Singh, Olivia
AU - Sundaravadanam, Yogi
AU - Rath, Prisni
AU - Sestini, Roberta
AU - Gensini, Francesca
AU - Agnihotri, Sameer
AU - Blakeley, Jaishri
AU - Ostrow, Kimberly
AU - Largaespada, David
AU - Plotkin, Scott R.
AU - Stemmer-Rachamimov, Anat
AU - Ferrer, Marcela Maria
AU - Pugh, Trevor J.
AU - Aldape, Kenneth D.
AU - Papi, Laura
AU - Zadeh, Gelareh
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Genomics
KW - LZTR1
KW - MAPK
KW - Pain
KW - Peripheral nerve sheath tumors
KW - Schwannomatosis
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U2 - 10.1007/s00401-020-02230-x
DO - 10.1007/s00401-020-02230-x
M3 - Article
C2 - 33025139
AN - SCOPUS:85092106294
SN - 0001-6322
VL - 141
SP - 101
EP - 116
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 1
ER -