Agnihotri, Sameer, Jalali, Shahrzad, Wilson, Mark R., Danesh, Arnavaz, Li, Mira, Klironomos, George, Krieger, Jonathan R., Mansouri, Alireza ORCID: 0000-0002-7442-7539, Khan, Osaama, Mamatjan, Yasin, Landon-Brace, Natalie, Tung, Takyee, Dowar, Mark, Li, Tiantian, Bruce, Jeffrey P., Burrell, Kelly E., Tonge, Peter D., Alamsahebpour, Amir, Krischek, Boris, Agarwalla, Pankaj Kumar, Bi, Wenya Linda, Dunn, Ian F., Beroukhim, Rameen, Fehlings, Michael G., Bril, Vera, Pagnotta, Stefano M., Iavarone, Antonio ORCID: 0000-0002-0683-4634, Pugh, Trevor J., Aldape, Kenneth D. and Zadeh, Gelareh (2016). The genomic landscape of schwannoma. Nature Genet., 48 (11). S. 1339 - 1349. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Agnihotri, SameerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jalali, ShahrzadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilson, Mark R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Danesh, ArnavazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, MiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klironomos, GeorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krieger, Jonathan R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mansouri, AlirezaUNSPECIFIEDorcid.org/0000-0002-7442-7539UNSPECIFIED
Khan, OsaamaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mamatjan, YasinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landon-Brace, NatalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tung, TakyeeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dowar, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, TiantianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruce, Jeffrey P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burrell, Kelly E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tonge, Peter D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alamsahebpour, AmirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krischek, BorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Agarwalla, Pankaj KumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bi, Wenya LindaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dunn, Ian F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beroukhim, RameenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fehlings, Michael G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bril, VeraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pagnotta, Stefano M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iavarone, AntonioUNSPECIFIEDorcid.org/0000-0002-0683-4634UNSPECIFIED
Pugh, Trevor J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aldape, Kenneth D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zadeh, GelarehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-257918
DOI: 10.1038/ng.3688
Journal or Publication Title: Nature Genet.
Volume: 48
Number: 11
Page Range: S. 1339 - 1349
Date: 2016
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DRIVER MUTATIONS; GENE-EXPRESSION; CANCER; TUMORS; CLASSIFICATION; ADENOCARCINOMA; ESTABLISHMENT; COMPLEXITY; RESISTANCE; INHIBITORSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25791

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