TY - JOUR
T1 - Genetic alterations in uncommon low-grade neuroepithelial tumors
T2 - BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology
AU - Qaddoumi, Ibrahim
AU - Orisme, Wilda
AU - Wen, Ji
AU - Santiago, Teresa
AU - Gupta, Kirti
AU - Dalton, James D.
AU - Tang, Bo
AU - Haupfear, Kelly
AU - Punchihewa, Chandanamali
AU - Easton, John
AU - Mulder, Heather
AU - Boggs, Kristy
AU - Shao, Ying
AU - Rusch, Michael
AU - Becksfort, Jared
AU - Gupta, Pankaj
AU - Wang, Shuoguo
AU - Lee, Ryan P.
AU - Brat, Daniel
AU - Peter Collins, V.
AU - Dahiya, Sonika
AU - George, David
AU - Konomos, William
AU - Kurian, Kathreena M.
AU - McFadden, Kathryn
AU - Serafini, Luciano Neder
AU - Nickols, Hilary
AU - Perry, Arie
AU - Shurtleff, Sheila
AU - Gajjar, Amar
AU - Boop, Fredrick A.
AU - Klimo, Paul D.
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Baker, Suzanne J.
AU - Zhang, Jinghui
AU - Wu, Gang
AU - Downing, James R.
AU - Tatevossian, Ruth G.
AU - Ellison, David W.
N1 - Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - BRAF
KW - FGFR1
KW - Glioma
KW - Glioneuronal
KW - MYB
KW - RNA-seq
UR - http://www.scopus.com/inward/record.url?scp=84955315769&partnerID=8YFLogxK
U2 - 10.1007/s00401-016-1539-z
DO - 10.1007/s00401-016-1539-z
M3 - Article
C2 - 26810070
AN - SCOPUS:84955315769
SN - 0001-6322
VL - 131
SP - 833
EP - 845
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -