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 Agarwalla; Wenya 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

doi:10.1038/ng.3688

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

^*Corresponding author for this work

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

115 Scopus citations

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 language	English (US)
Pages (from-to)	1339-1348
Number of pages	10
Journal	Nature Genetics
Volume	48
Issue number	11
DOIs	https://doi.org/10.1038/ng.3688
State	Published - Nov 1 2016

ASJC Scopus subject areas

Genetics

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Agnihotri, S., Jalali, S., Wilson, M. R., Danesh, A., Li, M., Klironomos, G., Krieger, J. R., Mansouri, A., Khan, O., Mamatjan, Y., Landon-Brace, N., Tung, T., Dowar, M., Li, T., Bruce, J. P., Burrell, K. E., Tonge, P. D., Alamsahebpour, A., Krischek, B., ... Zadeh, G. (2016). The genomic landscape of schwannoma. Nature Genetics, 48(11), 1339-1348. https://doi.org/10.1038/ng.3688

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title = "The genomic landscape of schwannoma",

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.",

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

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Agnihotri, S, Jalali, S, Wilson, MR, Danesh, A, Li, M, Klironomos, G, Krieger, JR, Mansouri, A, 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

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AU - Agnihotri, Sameer

AU - Jalali, Shahrzad

AU - Wilson, Mark R.

AU - Danesh, Arnavaz

AU - Li, Mira

AU - Klironomos, George

AU - Krieger, Jonathan R.

AU - Mansouri, 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.

AU - Alamsahebpour, Amir

AU - Krischek, Boris

AU - Agarwalla, Pankaj Kumar

AU - Bi, Wenya Linda

AU - Dunn, Ian F.

AU - Beroukhim, Rameen

AU - Fehlings, Michael G.

AU - Bril, Vera

AU - Pagnotta, Stefano M.

AU - Iavarone, Antonio

AU - Pugh, Trevor J.

AU - Aldape, Kenneth D.

AU - Zadeh, Gelareh

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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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The genomic landscape of schwannoma

Abstract

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