The genomic landscape of schwannoma

Sameer Agnihotri, Shahrzad Jalali, Mark R. Wilson, Arnavaz Danesh, Mira Li, George Klironomos, Jonathan R. Krieger, Seyed 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 journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1339-1348
Number of pages10
JournalNature Genetics
Volume48
Issue number11
DOIs
StatePublished - Nov 1 2016

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Neurilemmoma
Nerve Sheath Neoplasms
Exome
RNA Sequence Analysis
MAP Kinase Signaling System
Schwann Cells
DNA Sequence Analysis
Methylation
Sequence Analysis
Carcinogenesis
Chromosomes
Morbidity
Mutation
Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Agnihotri, S., Jalali, S., Wilson, M. R., Danesh, A., Li, M., Klironomos, G., ... Zadeh, G. (2016). The genomic landscape of schwannoma. Nature Genetics, 48(11), 1339-1348. https://doi.org/10.1038/ng.3688
Agnihotri, Sameer ; Jalali, Shahrzad ; Wilson, Mark R. ; Danesh, Arnavaz ; Li, Mira ; Klironomos, George ; Krieger, Jonathan R. ; Mansouri, Seyed Alireza ; 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 ; Pugh, Trevor J. ; Aldape, Kenneth D. ; Zadeh, Gelareh. / The genomic landscape of schwannoma. In: Nature Genetics. 2016 ; Vol. 48, No. 11. pp. 1339-1348.
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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.",
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Agnihotri, S, Jalali, S, Wilson, MR, Danesh, A, Li, M, Klironomos, G, Krieger, JR, Mansouri, SA, Khan, O, Mamatjan, Y, Landon-Brace, N, Tung, T, Dowar, M, Li, T, Bruce, JP, Burrell, KE, Tonge, PD, Alamsahebpour, A, Krischek, B, Agarwalla, PK, Bi, WL, Dunn, IF, Beroukhim, R, Fehlings, MG, Bril, V, Pagnotta, SM, Iavarone, A, Pugh, TJ, Aldape, KD & Zadeh, G 2016, 'The genomic landscape of schwannoma', Nature Genetics, vol. 48, no. 11, pp. 1339-1348. https://doi.org/10.1038/ng.3688

The genomic landscape of schwannoma. / Agnihotri, Sameer; Jalali, Shahrzad; Wilson, Mark R.; Danesh, Arnavaz; Li, Mira; Klironomos, George; Krieger, Jonathan R.; Mansouri, Seyed Alireza; 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; Pugh, Trevor J.; Aldape, Kenneth D.; Zadeh, Gelareh.

In: Nature Genetics, Vol. 48, No. 11, 01.11.2016, p. 1339-1348.

Research output: Contribution to journalArticle

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AU - Jalali, Shahrzad

AU - Wilson, Mark R.

AU - Danesh, Arnavaz

AU - Li, Mira

AU - Klironomos, George

AU - Krieger, Jonathan R.

AU - Mansouri, Seyed Alireza

AU - Khan, Osaama

AU - Mamatjan, Yasin

AU - Landon-Brace, Natalie

AU - Tung, Takyee

AU - Dowar, Mark

AU - Li, Tiantian

AU - Bruce, Jeffrey P.

AU - Burrell, Kelly E.

AU - Tonge, Peter D.

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AU - Agarwalla, Pankaj Kumar

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AU - Beroukhim, Rameen

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Agnihotri S, Jalali S, Wilson MR, Danesh A, Li M, Klironomos G et al. The genomic landscape of schwannoma. Nature Genetics. 2016 Nov 1;48(11):1339-1348. https://doi.org/10.1038/ng.3688