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25.01.2016 | Original Paper

Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology

verfasst von: Ibrahim Qaddoumi, Wilda Orisme, Ji Wen, Teresa Santiago, Kirti Gupta, James D. Dalton, Bo Tang, Kelly Haupfear, Chandanamali Punchihewa, John Easton, Heather Mulder, Kristy Boggs, Ying Shao, Michael Rusch, Jared Becksfort, Pankaj Gupta, Shuoguo Wang, Ryan P. Lee, Daniel Brat, V. Peter Collins, Sonika Dahiya, David George, William Konomos, Kathreena M. Kurian, Kathryn McFadden, Luciano Neder Serafini, Hilary Nickols, Arie Perry, Sheila Shurtleff, Amar Gajjar, Fredrick A. Boop, Paul D. Klimo Jr., Elaine R. Mardis, Richard K. Wilson, Suzanne J. Baker, Jinghui Zhang, Gang Wu, James R. Downing, Ruth G. Tatevossian, David W. Ellison

Erschienen in: Acta Neuropathologica | Ausgabe 6/2016

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Abstract

Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and ‘adult-type’ diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.

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Titel: Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology
verfasst von: Ibrahim Qaddoumi
Wilda Orisme
Ji Wen
Teresa Santiago
Kirti Gupta
James D. Dalton
Bo Tang
Kelly Haupfear
Chandanamali Punchihewa
John Easton
Heather Mulder
Kristy Boggs
Ying Shao
Michael Rusch
Jared Becksfort
Pankaj Gupta
Shuoguo Wang
Ryan P. Lee
Daniel Brat
V. Peter Collins
Sonika Dahiya
David George
William Konomos
Kathreena M. Kurian
Kathryn McFadden
Luciano Neder Serafini
Hilary Nickols
Arie Perry
Sheila Shurtleff
Amar Gajjar
Fredrick A. Boop
Paul D. Klimo Jr.
Elaine R. Mardis
Richard K. Wilson
Suzanne J. Baker
Jinghui Zhang
Gang Wu
James R. Downing
Ruth G. Tatevossian
David W. Ellison
Publikationsdatum: 25.01.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 6/2016
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-016-1539-z

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