| Literature DB >> 27723760 |
Sameer Agnihotri1, Shahrzad Jalali1, Mark R Wilson1, Arnavaz Danesh2, Mira Li1, George Klironomos1, Jonathan R Krieger3, Alireza Mansouri1, Osaama Khan1, Yasin Mamatjan1, Natalie Landon-Brace1, Takyee Tung1, Mark Dowar2, Tiantian Li2, Jeffrey P Bruce2, Kelly E Burrell1, Peter D Tonge1, Amir Alamsahebpour1, Boris Krischek4, Pankaj Kumar Agarwalla5,6,7,8, Wenya Linda Bi5,6,8,9, Ian F Dunn5,9, Rameen Beroukhim5,6,8,9,10, Michael G Fehlings11, Vera Bril12, Stefano M Pagnotta13,14, Antonio Iavarone14, Trevor J Pugh2,15, Kenneth D Aldape1,2,15,16,17, Gelareh Zadeh1,2,11.
Abstract
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.Entities:
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Year: 2016 PMID： 27723760 DOI： 10.1038/ng.3688
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330