Skip to main content

Advertisement

Log in

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

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Arita H, Narita Y, Fukushima S, Tateishi K, Matsushita Y, Yoshida A et al (2013) Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 126:267–276. https://doi.org/10.1007/s00401-013-1141-6

    Article  CAS  PubMed  Google Scholar 

  2. Bell RJ, Rube HT, Xavier-Magalhaes A, Costa BM, Mancini A, Song JS et al (2016) Understanding TERT promoter mutations: a common path to immortality. Mol Cancer Res 14:315–323. https://doi.org/10.1158/1541-7786.MCR-16-0003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bigner SH, Burger PC, Wong AJ, Werner MH, Hamilton SR, Muhlbaier LH et al (1988) Gene amplification in malignant human gliomas: clinical and histopathologic aspects. J Neuropathol Exp Neurol 47:191–205

    Article  CAS  Google Scholar 

  4. Bigner SH, Mark J, Burger PC, Mahaley SM, Bullard DEJ, Muhlbaier LH et al (1988) Specific chromosomal abnormalities in malignant human gliomas. Can Res 48:405–411

    CAS  Google Scholar 

  5. Cancer Genome Atlas Research N, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498. https://doi.org/10.1056/nejmoa1402121

    Article  Google Scholar 

  6. Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474. https://doi.org/10.1038/nature26000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA et al (2016) Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164:550–563. https://doi.org/10.1016/j.cell.2015.12.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H et al (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:2499–2508. https://doi.org/10.1056/NEJMoa1407279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ekstrand AJ, James CD, Cavenee WK, Seliger B, Petterson RF, Collins VP (1991) Genes for epidermal growth factor receptor, transforming growth factor α, and epidermal growth factor and their expression in human gliomas in vivo. Can Res 51:2164–2172

    CAS  Google Scholar 

  10. Goutagny S, Nault JC, Mallet M, Henin D, Rossi JZ, Kalamarides M (2014) High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol 24:184–189. https://doi.org/10.1111/bpa.12110

    Article  CAS  PubMed  Google Scholar 

  11. Hasselblatt M, Jaber M, Reuss D, Grauer O, Bibo A, Terwey S et al (2018) Diffuse astrocytoma, IDH-wildtype: a dissolving diagnosis. J Neuropathol Exp Neurol 77:422–425. https://doi.org/10.1093/jnen/nly012

    Article  PubMed  Google Scholar 

  12. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A et al (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339:959–961. https://doi.org/10.1126/science.1230062

    Article  CAS  PubMed  Google Scholar 

  13. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–959. https://doi.org/10.1126/science.1229259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr et al (2013) TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA 110:6021–6026. https://doi.org/10.1073/pnas.1303607110

    Article  CAS  PubMed  Google Scholar 

  15. Koelsche C, Renner M, Hartmann W, Brandt R, Lehner B, Waldburger N et al (2014) TERT promoter hotspot mutations are recurrent in myxoid liposarcomas but rare in other soft tissue sarcoma entities. J Exp Clin Cancer Res 33:33. https://doi.org/10.1186/1756-9966-33-33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Koelsche C, Sahm F, Capper D, Reuss D, Sturm D, Jones DT et al (2013) Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathol 126:907–915. https://doi.org/10.1007/s00401-013-1195-5

    Article  CAS  PubMed  Google Scholar 

  17. Korshunov A, Chavez L, Sharma T, Ryzhova M, Schrimpf D, Stichel D et al (2017) Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis. Brain Pathol. https://doi.org/10.1111/bpa.12566 (Epub ahead of print)

    Article  PubMed  Google Scholar 

  18. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H et al (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor in primary human brain tumors of glial origin. Nature 313:144–147

    Article  CAS  Google Scholar 

  19. Liu X, Wu G, Shan Y, Hartmann C, von Deimling A, Xing M (2013) Highly prevalent TERT promoter mutations in bladder cancer and gliobastoma. Cell Cycle 12:1637–1638

    Article  CAS  Google Scholar 

  20. Louis D, Ohgaki H, Wiestler O, Cavenee WK (2016) World health organization classification of tumours of the central nervous system. In: Bosman F, Jaffe E, Lakhani S, Ohgaki H (eds) World health organization classification of tumours revised 4th edition. IARC, Lyon

    Google Scholar 

  21. Nonoguchi N, Ohta T, Oh JE, Kim YH, Kleihues P, Ohgaki H (2013) TERT promoter mutations in primary and secondary glioblastomas. Acta Neuropathol 126:931–937. https://doi.org/10.1007/s00401-013-1163-0

    Article  CAS  PubMed  Google Scholar 

  22. Pekmezci M, Rice T, Molinaro AM, Walsh KM, Decker PA, Hansen H et al (2017) Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT. Acta Neuropathol 133:1001–1016. https://doi.org/10.1007/s00401-017-1690-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Remke M, Ramaswamy V, Peacock J, Shih DJ, Koelsche C, Northcott PA et al (2013) TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathol 126:917–929. https://doi.org/10.1007/s00401-013-1198-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Reuss DE, Kratz A, Sahm F, Capper D, Schrimpf D, Koelsche C et al (2015) Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathol 130:407–417. https://doi.org/10.1007/s00401-015-1454-8

    Article  CAS  PubMed  Google Scholar 

  25. Rey JA, Bello MJ, de Campos JM, Kusak E, Ramos C, Benitez J (1987) Chromosomal patterns in human malignant astrocytoma. Cancer Genet Cytogenet 29:201–221

    Article  CAS  Google Scholar 

  26. Sahm F, Schrimpf D, Jones DT, Meyer J, Kratz A, Reuss D et al (2016) Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol 131:903–910. https://doi.org/10.1007/s00401-015-1519-8

    Article  CAS  PubMed  Google Scholar 

  27. Sahm F, Schrimpf D, Olar A, Koelsche C, Reuss D, Bissel J et al (2015) TERT promoter mutations and risk of recurrence in meningioma. J Natl Cancer Inst 108:djv377. https://doi.org/10.1093/jnci/djv377

    Article  CAS  PubMed Central  Google Scholar 

  28. Sauter G, Maeda T, Waldman FM, Davis RL, Feuerstein BG (1996) Patterns of epidermal growth factor receptor amplification in malignant gliomas. Am J Pathol 148:1047–1053

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C et al (2011) Analysis of BRAF V600E mutation in 1320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma and ganglioglioma. Acta Neuropathol 121:397–405

    Article  CAS  Google Scholar 

  30. Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss DE, Sahm F et al (2018) Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol 136:255–271. https://doi.org/10.1007/s00401-018-1849-4

    Article  CAS  Google Scholar 

  31. Sun Y, Zhang W, Chen D, Lv Y, Zheng J, Lilljebjorn H et al (2014) A glioma classification scheme based on coexpression modules of EGFR and PDGFRA. Proc Natl Acad Sci USA 111:3538–3543. https://doi.org/10.1073/pnas.1313814111

    Article  CAS  PubMed  Google Scholar 

  32. Suzuki H, Aoki K, Chiba K, Sato Y, Shiozawa Y, Shiraishi Y et al (2015) Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 47:458–468. https://doi.org/10.1038/ng.3273

    Article  CAS  PubMed  Google Scholar 

  33. Vinagre J, Almeida A, Populo H, Batista R, Lyra J, Pinto V et al (2013) Frequency of TERT promoter mutations in human cancers. Nat Commun 4:1–6. https://doi.org/10.1038/ncomms3185

    Article  CAS  Google Scholar 

  34. Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84:6899–6903

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andreas von Deimling.

Electronic supplementary material

Below is the link to the electronic supplementary material.

401_2018_1905_MOESM1_ESM.xlsx

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

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

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stichel, D., Ebrahimi, A., Reuss, D. et al. 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. Acta Neuropathol 136, 793–803 (2018). https://doi.org/10.1007/s00401-018-1905-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-018-1905-0

Keywords

Navigation