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 McBain; Myra 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

doi:10.1093/neuonc/noab088

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

Neuro Oncol. 2021 Sep 1;23(9):1547-1559. doi: 10.1093/neuonc/noab088.

Authors

C Mircea S Tesileanu¹, Martin J van den Bent¹, Marc Sanson², Wolfgang Wick³, Alba A Brandes⁴, Paul M Clement⁵, Sara C Erridge⁶, Michael A Vogelbaum⁷, Anna K Nowak^{8

9

10}, Jean F Baurain¹¹, Warren P Mason¹², Helen Wheeler¹³, Olivier L Chinot¹⁴, Sanjeev Gill¹⁵, Matthew Griffin¹⁶, Leland Rogers¹⁷, Walter Taal¹, Roberta Rudà¹⁸, Michael Weller¹⁹, Catherine McBain²⁰, Myra E van Linde²¹, Thais S Sabedot²², Youri Hoogstrate¹, Andreas von Deimling^{23

24}, Iris de Heer¹, Wilfred F J van IJcken²⁵, Rutger W W Brouwer²⁵, Kenneth Aldape¹², Robert B Jenkins²⁶, Hendrikus J Dubbink²⁷, Johan M Kros²⁷, Pieter Wesseling^{28

29}, Kin Jip Cheung³⁰, Vassilis Golfinopoulos³⁰, Brigitta G Baumert^{31

32}, Thierry Gorlia³⁰, Houtan Noushmehr²², Pim J French¹

Affiliations

¹ Neurology Department, Erasmus MC, Rotterdam, the Netherlands.
² Sorbonne Université, Hôpitaux Universitaires La Pitié Salpêtrière, Paris, France.
³ Neurology Department, Universitätsklinikum Heidelberg, Heidelberg, Germany.
⁴ Medical Oncology Department, AUSL-IRCCS Scienze Neurologiche, Bologna, Italy.
⁵ Oncology Department, KU Leuven and Medical Oncology Department, UZ Leuven, Leuven, Belgium.
⁶ Neuro-Oncology Centre Edinburgh, Western General Hospital, Edinburgh, UK.
⁷ Neuro-Oncology Department, Moffitt Cancer Center, Tampa, Florida, USA.
⁸ University of Western Australia, Perth, Australia.
⁹ Co-Operative Group for Neuro-Oncology, University of Sydney, Sydney, Australia.
¹⁰ Medical Oncology Department, Sir Charles Gairdner Hospital, Nedlands, Australia.
¹¹ Medical Oncology Department, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Brussels, Belgium.
¹² Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
¹³ Northern Sydney Cancer Centre, Sydney, Australia.
¹⁴ Neuro-Oncology Department, Aix-Marseille University, Marseille, France.
¹⁵ Medical Oncology Department, Alfred Hospital, Melbourne, Australia.
¹⁶ Clinical Oncology Department, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹⁷ Radiation Oncology Department, Gammawest Cancer Services, Salt Lake City, Utah, USA.
¹⁸ Neuro-Oncology Department, University of Turin, Turin, Italy.
¹⁹ Neurology Department, University Hospital of Zurich, Zurich, Switzerland.
²⁰ Clinical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK.
²¹ Medical Oncology Department, Amsterdam UMC, Amsterdam, the Netherlands.
²² Neurosurgery Department, Henry Ford Health System, Detroit, Michigan, USA.
²³ Neuropathology Department, Ruprecht-Karls-University, Heidelberg, Germany.
²⁴ Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁵ Biomics Center, Erasmus MC, Rotterdam, the Netherlands.
²⁶ Pathology Department, Mayo Clinic, Rochester, Minnesota, USA.
²⁷ Pathology Department, Erasmus MC, Rotterdam, the Netherlands.
²⁸ Pathology Department, Amsterdam UMC, Amsterdam, the Netherlands.
²⁹ Princess Máxima Center, Utrecht, the Netherlands.
³⁰ EORTC HQ, Brussels, Belgium.
³¹ Radiation Oncology Department, Maastricht UMC, Maastricht, the Netherlands.
³² Radiation Oncology Institute, Cantonal Hospital Graubünden, Chur, Switzerland.

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.

Keywords: IDH mutant; 1p/19q non-codeleted; DNA methylation profiling; anaplastic glioma; patient prognostication.

Publication types

Clinical Trial, Phase III
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Brain Neoplasms* / genetics
Brain Neoplasms* / therapy
Chromosomes, Human, Pair 1
DNA Copy Number Variations
DNA Methylation
Glioma* / genetics
Glioma* / therapy
Homozygote
Humans
Isocitrate Dehydrogenase / genetics
Mutation
Prognosis
Prospective Studies
Sequence Deletion

Substances

Isocitrate Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding