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Prognostic Significance of DNA Methylation Profiles at MRI Enhancing Tumor Recurrence: a Report from the EORTC 26091 TAVAREC Trial.

  • Draaisma, Kaspar1
  • Tesileanu, C Mircea S1
  • de Heer, Iris1
  • Klein, Martin2
  • Smits, Marion3
  • Reijneveld, Jaap C2, 4
  • Clement, Paul M5
  • de Vos, Filip Y F6
  • Wick, Antje7
  • Mulholland, Paul J8
  • Taphoorn, Martin J B9, 10
  • Weller, Michael11
  • Chinot, Olivier L12
  • Kros, Johan M13
  • Verschuere, Tina14
  • Coens, Corneel14
  • Golfinopoulos, Vassilis14
  • Gorlia, Thierry14
  • Idbaih, Ahmed15
  • Robe, Pierre A6
  • And 2 more
  • 1 Department of Neurology, Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. , (Netherlands)
  • 2 Amsterdam UMC - Location VUmc, Amsterdam, the Netherlands. , (Netherlands)
  • 3 Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands. , (Netherlands)
  • 4 Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands. , (Netherlands)
  • 5 Department of Oncology, KU Leuven, Leuven Cancer Institute, Leuven, Belgium. , (Belgium)
  • 6 UMC Utrecht, Utrecht, the Netherlands. , (Netherlands)
  • 7 Heidelberg University MC, Heidelberg, Germany. , (Germany)
  • 8 University College, London, United Kingdom. , (United Kingdom)
  • 9 MC Haaglanden, The Hague, the Netherlands. , (Netherlands)
  • 10 Leiden UMC, Leiden, the Netherlands. , (Netherlands)
  • 11 University Hospital Zurich, Zurich, Switzerland. , (Switzerland)
  • 12 Hôpital de la Timone, Marseille, France. , (France)
  • 13 Department of Pathology, Erasmus MC, Rotterdam, the Netherlands. , (Netherlands)
  • 14 EORTC Headquarters, Brussels, Belgium. , (Belgium)
  • 15 Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, DMU Neurosciences, Paris, France. , (France)
Published Article
Clinical Cancer Research
American Association for Cancer Research
Publication Date
Jun 01, 2022
DOI: 10.1158/1078-0432.CCR-21-3725
PMID: 35294545


Despite recent advances in the molecular characterization of gliomas, it remains unclear which patients benefit most from which second-line treatments. The TAVAREC trial was a randomized, open-label phase II trial assessing the benefit of the addition of the angiogenesis inhibitor bevacizumab to treatment with temozolomide in patients with a first enhancing recurrence of World Health Organization grade 2 or 3 glioma without 1p/19q codeletion. We evaluated the prognostic significance of genome-wide DNA methylation profiles and copy-number variations on the TAVAREC trial samples. Isocitrate dehydrogenase (IDH) mutation status was determined via Sanger sequencing and IHC. DNA methylation analysis was performed using the MethylationEPIC BeadChip (Illumina) from which 1p/19q codeletion, MGMT promoter methylation (MGMT-STP27), and homozygous deletion of CDKN2A/B were determined. DNA methylation classes were determined according to classifiers developed in Heidelberg and The Cancer Genome Atlas (TCGA; "Heidelberg" and "TCGA" classifier respectively). DNA methylation profiles of 122 samples were successfully determined. As expected, most samples were IDH-mutant (89/122) and MGMT promotor methylated (89/122). Methylation classes were prognostic for time to progression. However, Heidelberg methylation classes determined at time of diagnosis were no longer prognostic following enhancing recurrence of the tumor. In contrast, TCGA methylation classes of primary samples remained prognostic also following enhancing recurrence. Homozygous deletions in CDKN2A/B were found in 10 of 87 IDH-mutated samples and were prognostically unfavorable at recurrence. DNA methylome Heidelberg classification at time of diagnosis is no longer of prognostic value at the time of enhancing recurrence. CDKN2A/B deletion status was predictive of survival from progression of IDH-mutated tumors. ©2022 American Association for Cancer Research.

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