Abstract
According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AIIIDHmut), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIIIIDHmut), and WHO grade IV glioblastoma, IDH-mutant (GBMIDHmut). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AIIIDHmut and AAIIIIDHmut have lost their significance. In contrast, GBMIDHmut still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.
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Acknowledgements
This work was supported by German Cancer Aid (70112371) to AvD and German Cancer Aid (110624) to WW and MW. We are indebted to Toshio Sasajima, Masaya Oda and Masataka Takahashi for support regarding clinical data acquisition. We thank Viktoria Zeller, Ulrike Lass, Antje Habel, Ulrike Vogel, Katja Brast, Kerstin Lindenberg, John Moyers 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), especially Matthias Schick, Roger Fischer, Nadja Wermke and Anja Schramm-Glück, for providing methylation services.
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401_2018_1849_MOESM1_ESM.pptx
Supplementary Fig. 1 Copy number summary plots. Vertical axis indicates percentage of patients affected. Horizontal axis refers to chromosomal localization. Dotted vertical lines indicate border between p and q arms. Data are given for three age groups (PPTX 352 kb)
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Supplementary Fig. 2 Kaplan–Meier plots stratifying by unsupervised clustering in the discovery set (a), the HD validation set (b) and the EORTC validation set (c). Kaplan–Meier plots stratifying by the methylation based classifier in the discovery set (d), the HD validation set (e) and the EORTC validation set (f) (PPTX 280 kb)
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Supplementary Fig. 3 OS of subgroups in Modelcombined. The patient set (n = 7) characterized by necrosis, absence of CDKN2A/B homozygous deletion and low CNVL exhibited only 2 events. While the corresponding curve (red) fits well the group of patients with intermediate OS, the number is too low for a clear statement (PPTX 150 kb)
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Supplementary Fig. 4 Association of proliferation markers with CDKN2A/B status. (a) association with Ki67. (b) association with pHH3. Horizontal bars in box-plots correspond to median values (PPTX 166 kb)
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Supplementary Fig. 5 OS of patients with IDH-mutant astrocytoma in association with RB pathway genes. (a) red -homozygous deletion of CDKN2A/B, black – wild type status. (b) red –homozygous deletion of RB1 or CDK4 amplification or CDK6 amplification, black – wild type status.. (a) red -homozygous deletion of CDKN2A/B or homozygous deletion of RB1 or CDK4 amplification or CDK6 amplification, black – wild type status for all (PPTX 100 kb)
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Supplementary Table 1 Discovery set data employed in grading schemes for IDH-mutant astrocytoma. For each scheme lowest grade is indicated by green, intermediate grade by blue and highest grade by red color (DOCX 66 kb)
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Supplementary Table 2 Possible designation of IDH-mutant astrocytoma based on Modelpath in a future classification scheme (DOCX 13 kb)
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Shirahata, M., Ono, T., Stichel, D. et al. Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol 136, 153–166 (2018). https://doi.org/10.1007/s00401-018-1849-4
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DOI: https://doi.org/10.1007/s00401-018-1849-4