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Acta Neuropathologica

, Volume 136, Issue 5, pp 793–803 | Cite as

Distribution of EGFR amplification, combined chromosome 7 gain and chromosome 10 loss, and TERT promoter mutation in brain tumors and their potential for the reclassification of IDHwt astrocytoma to glioblastoma

  • Damian Stichel
  • Azadeh Ebrahimi
  • David Reuss
  • Daniel Schrimpf
  • Takahiro Ono
  • Mitsuaki Shirahata
  • Guido Reifenberger
  • Michael Weller
  • Daniel Hänggi
  • Wolfgang Wick
  • Christel Herold-Mende
  • Manfred Westphal
  • Sebastian Brandner
  • Stefan M. Pfister
  • David Capper
  • Felix Sahm
  • Andreas von DeimlingEmail author
Original Paper

Abstract

EGFR amplification (EGFRamp), the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10−), and TERT promoter mutation (pTERTmut) are alterations frequently observed in adult IDH-wild-type (IDHwt) glioblastoma (GBM). In the absence of endothelial proliferation and/or necrosis, these alterations currently are considered to serve as a surrogate for upgrading IDHwt diffuse or anaplastic astrocytoma to GBM. Here, we set out to determine the distribution of EGFRamp, 7+/10−, and pTERTmut by analyzing high-resolution copy-number profiles and next-generation sequencing data of primary brain tumors. In addition, we addressed the question whether combinations of partial gains on chromosome 7 and partial losses on chromosome 10 exhibited a diagnostic and prognostic value similar to that of complete 7+/10−. Several such combinations proved relevant and were combined as the 7/10 signature. Our results demonstrate that EGFRamp and the 7/10 signature are closely associated with IDHwt GBM. In contrast, pTERTmut is less specific for IDHwt GBM. We conclude that, in the absence of endothelial proliferation and/or necrosis, the detection of EGFRamp is a very strong surrogate marker for the diagnosis of GBM in IDHwt diffuse astrocytic tumors. The 7/10 signature is also a strong surrogate marker. However, care should be taken to exclude pleomorphic xanthoastrocytoma. pTERTmut is less restricted to this entity and needs companion analysis by other molecular markers to serve as a surrogate for diagnosing IDHwt GBM. A combination of any two of EGFRamp, the 7/10 signature and pTERTmut, is highly specific for IDHwt GBM and the combination of all three alterations is frequent and exclusively seen in IDHwt GBM.

Keywords

EGFR amplification Chromosome 7 gain Chromosome 10 loss 7+/10− 7+/10q− TERT promoter mutation Glioblastoma Astrocytoma Pleomorphic xanthoastrocytoma 

Notes

Acknowledgements

This work was supported by German Cancer Aid (70112371) to AvD. We thank Viktoria Zeller, Ulrike Lass, Antje Habel, Ulrike Vogel, Katja Brast, Kerstin Lindenberg, and Jochen Meyer for excellent technical assistance. We also thank the Microarray Unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), for providing DNA methylation services.

Supplementary material

401_2018_1905_MOESM1_ESM.xlsx (34 kb)
Supplementary table 1 Distribution of EGFRamp and status of chromosomes 7 and 10 in 10,826 tumors (cohort 2). Chromosome 7 and 10 status is given for two different thresholds requiring loss >50% or >80% of the respective arms. Combinations not qualifying for any form of a combined 7 gain and 10 losses are indicated by print in gray (XLSX 34 kb)
401_2018_1905_MOESM2_ESM.xlsx (11 kb)
Supplementary table 2 Distribution of methylation groups and alterations on chromosomes 7 and 10 as well as EGFR status in 939 patients from cohort 2 for whom survival data were available (XLSX 10 kb)
401_2018_1905_MOESM3_ESM.xlsx (11 kb)
Supplementary table 3 Methylation-based classification of 52 patients in cohort 3 without a 7/10 signature but with typical survival characteristics of GBM (XLSX 11 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Damian Stichel
    • 1
  • Azadeh Ebrahimi
    • 1
    • 2
  • David Reuss
    • 1
    • 2
  • Daniel Schrimpf
    • 1
    • 2
  • Takahiro Ono
    • 3
  • Mitsuaki Shirahata
    • 4
  • Guido Reifenberger
    • 5
    • 6
  • Michael Weller
    • 7
  • Daniel Hänggi
    • 8
  • Wolfgang Wick
    • 9
    • 10
  • Christel Herold-Mende
    • 11
  • Manfred Westphal
    • 12
  • Sebastian Brandner
    • 13
    • 14
  • Stefan M. Pfister
    • 15
    • 16
    • 17
  • David Capper
    • 1
    • 2
    • 18
    • 19
    • 20
  • Felix Sahm
    • 1
    • 2
  • Andreas von Deimling
    • 1
    • 2
    Email author
  1. 1.Clinical Cooperation Unit NeuropathologyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Department of Neuropathology, Institute of PathologyHeidelberg University HospitalHeidelbergGermany
  3. 3.Department of NeurosurgeryAkita University Graduate School of MedicineAkitaJapan
  4. 4.Department of Neuro-Oncology/NeurosurgerySaitama Medical University International Medical CenterHidakaJapan
  5. 5.Department of NeuropathologyHeinrich Heine UniversityDüsseldorfGermany
  6. 6.German Cancer Consortium (DKTK), Partner Site Essen/DüsseldorfDüsseldorfGermany
  7. 7.Department of NeurologyUniversity Hospital and University of ZurichZurichSwitzerland
  8. 8.Department of NeurosurgeryUniversity Medical Center Mannheim, University of HeidelbergHeidelbergGermany
  9. 9.Department of NeurologyHeidelberg University HospitalHeidelbergGermany
  10. 10.Clinical Cooperation Unit NeurooncologyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  11. 11.Department of NeurosurgeryHeidelberg University HospitalHeidelbergGermany
  12. 12.Department of NeurosurgeryUniversity Hamburg-EppendorfHamburgGermany
  13. 13.Division of Neuropathology, The National Hospital for Neurology and NeurosurgeryUniversity College London NHS Foundation TrustLondonUK
  14. 14.Department of NeurodegenerationUCL Institute of NeurologyLondonUK
  15. 15.Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)HeidelbergGermany
  16. 16.Division of Pediatric NeurooncologyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  17. 17.Department of Pediatric Oncology, Hematology and ImmunologyUniversity Hospital HeidelbergHeidelbergGermany
  18. 18.German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ) HeidelbergHeidelbergGermany
  19. 19.Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu BerlinBerlinGermany
  20. 20.Department of NeuropathologyBerlin Institute of HealthBerlinGermany

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