Acta Neuropathologica

, Volume 131, Issue 6, pp 833–845 | Cite as

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

  • 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. KlimoJr.
  • Elaine R. Mardis
  • Richard K. Wilson
  • Suzanne J. Baker
  • Jinghui Zhang
  • Gang Wu
  • James R. Downing
  • Ruth G. Tatevossian
  • David W. Ellison
Original Paper

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.

Keywords

Glioma Glioneuronal RNA-seq FGFR1 MYB BRAF 

Supplementary material

401_2016_1539_MOESM1_ESM.pdf (22.2 mb)
Supplementary material 1 (PDF 22684 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ibrahim Qaddoumi
    • 1
  • Wilda Orisme
    • 2
  • Ji Wen
    • 2
  • Teresa Santiago
    • 2
  • Kirti Gupta
    • 2
  • James D. Dalton
    • 2
  • Bo Tang
    • 2
  • Kelly Haupfear
    • 2
  • Chandanamali Punchihewa
    • 2
  • John Easton
    • 3
  • Heather Mulder
    • 3
  • Kristy Boggs
    • 3
  • Ying Shao
    • 3
  • Michael Rusch
    • 3
  • Jared Becksfort
    • 3
  • Pankaj Gupta
    • 3
  • Shuoguo Wang
    • 3
  • Ryan P. Lee
    • 2
  • Daniel Brat
    • 4
  • V. Peter Collins
    • 5
  • Sonika Dahiya
    • 6
  • David George
    • 7
  • William Konomos
    • 8
  • Kathreena M. Kurian
    • 9
  • Kathryn McFadden
    • 10
  • Luciano Neder Serafini
    • 11
  • Hilary Nickols
    • 12
  • Arie Perry
    • 13
  • Sheila Shurtleff
    • 2
  • Amar Gajjar
    • 1
  • Fredrick A. Boop
    • 14
  • Paul D. KlimoJr.
    • 14
  • Elaine R. Mardis
    • 6
  • Richard K. Wilson
    • 6
  • Suzanne J. Baker
    • 15
  • Jinghui Zhang
    • 3
  • Gang Wu
    • 3
  • James R. Downing
    • 2
  • Ruth G. Tatevossian
    • 2
  • David W. Ellison
    • 2
  1. 1.Department of OncologySt. Jude Children’s Research HospitalMemphisUSA
  2. 2.Department of PathologySt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of Computational BiologySt. Jude Children’s Research HospitalMemphisUSA
  4. 4.Department of PathologyEmory University School of MedicineAtlantaUSA
  5. 5.Department of PathologyUniversity of CambridgeCambridgeUK
  6. 6.Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisUSA
  7. 7.Department of PathologyFoothills Medical CenterLas CrucesUSA
  8. 8.Department of PathologyInnovative Pathology Services KnoxvilleKnoxvilleUSA
  9. 9.Department of PathologyFrenchay HospitalBristolUK
  10. 10.Department of PathologyUniversity of PittsburghPittsburghUSA
  11. 11.Department of PathologyUniversity of São Paulo, Ribeirão Preto School of MedicineSão PauloBrazil
  12. 12.Department of Pathology, Microbiology, and ImmunologyVanderbilt UniversityNashvilleUSA
  13. 13.Department of PathologyUniversity of California, San FranciscoSan FranciscoUSA
  14. 14.Department of SurgerySt. Jude Children’s Research HospitalMemphisUSA
  15. 15.Department of Developmental NeurobiologySt. Jude Children’s Research HospitalMemphisUSA

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