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