The genomic landscape of schwannoma

Sameer Agnihotri, Shahrzad Jalali, Mark R. Wilson, Arnavaz Danesh, Mira Li, George Klironomos, Jonathan R. Krieger, Alireza Mansouri, Osaama Khan, Yasin Mamatjan, Natalie Landon-Brace, Takyee Tung, Mark Dowar, Tiantian Li, Jeffrey P. Bruce, Kelly E. Burrell, Peter D. Tonge, Amir Alamsahebpour, Boris Krischek, Pankaj Kumar AgarwallaWenya Linda Bi, Ian F. Dunn, Rameen Beroukhim, Michael G. Fehlings, Vera Bril, Stefano M. Pagnotta, Antonio Iavarone, Trevor J. Pugh, Kenneth D. Aldape, Gelareh Zadeh

Research output: Contribution to journalArticlepeer-review

109 Scopus citations


Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.

Original languageEnglish (US)
Pages (from-to)1339-1348
Number of pages10
JournalNature Genetics
Issue number11
StatePublished - Nov 1 2016

All Science Journal Classification (ASJC) codes

  • Genetics


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