Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma

C. Mircea S. Tesileanu, Martin J. Van Den Bent, Marc Sanson, Wolfgang Wick, Alba A. Brandes, Paul M. Clement, Sara C. Erridge, Michael A. Vogelbaum, Anna K. Nowak, Jean F. Baurain, Warren P. Mason, Helen Wheeler, Olivier L. Chinot, Sanjeev Gill, Matthew Griffin, Leland Rogers, Walter Taal, Roberta Rudà, Michael Weller, Catherine McBainMyra E. Van Linde, Thais S. Sabedot, Youri Hoogstrate, Andreas Von Deimling, Iris De Heer, Wilfred F.J. Van Ijcken, Rutger W.W. Brouwer, Kenneth Aldape, Robert B. Jenkins, Hendrikus J. Dubbink, Johan M. Kros, Pieter Wesseling, Kin Jip Cheung, Vassilis Golfinopoulos, Brigitta G. Baumert, Thierry Gorlia, Houtan Noushmehr, Pim J. French*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

27 Citations (Scopus)
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Abstract

Background: Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. Methods: The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization. Results: Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Conclusion: Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.

Original languageEnglish
Pages (from-to)1547-1559
Number of pages13
JournalNeuro-Oncology
Volume23
Issue number9
DOIs
Publication statusPublished - 1 Sept 2021

Bibliographical note

Funding Information:
This study was supported by MSD (educational grant, provision of temozolomide), the NRG (grants U10CA180868 and U10CA180822), Cancer Research UK (grant CRUK/07/028), and Cancer Australia (grants 1026842 and 1078655). The molecular analysis was funded by The Brain Tumour Charity (grant GN- 000577), the Dutch Cancer Society (grant 10685), the Vereniging Heino "Strijd van Salland," and the USA Department of Defence (grant CA170278).

Publisher Copyright:
© 2021 The Author(s) 2021.

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