The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033

• Published in: Acta neuropathologica 2018-04, Vol.135 (4), p.601-615
• Main Authors: Bady, Pierre, Kurscheid, Sebastian, Delorenzi, Mauro, Gorlia, Thierry, van den Bent, Martin J., Hoang-Xuan, Khê, Vauléon, Élodie, Gijtenbeek, Anja, Enting, Roelien, Thiessen, Brian, Chinot, Olivier, Dhermain, Frédéric, Brandes, Alba A., Reijneveld, Jaap C., Marosi, Christine, Taphoorn, Martin J. B., Wick, Wolfgang, von Deimling, Andreas, French, Pim, Stupp, Roger, Baumert, Brigitta G., Hegi, Monika E.
• Format: Article
• Language: English
• Subjects: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Alkylating - therapeutic use; Brain Neoplasms; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Brain tumors; Cancer genetics; Care and treatment; Cognitive ability; CpG Islands; Deoxyribonucleic acid; Discoidin Domain Receptors; Discoidin Domain Receptors - genetics; DNA; DNA damage; DNA Methylation; DNA Methylation - drug effects; DNA Methylation - radiation effects; DNA Modification Methylases; DNA Modification Methylases - genetics; DNA Repair Enzymes; DNA Repair Enzymes - genetics; Epigenesis, Genetic; Female; Genes; Genomes; Genotoxicity; Glioma; Glioma - genetics; Glioma - pathology; Glioma - therapy; Humans; Isocitrate Dehydrogenase; Isocitrate Dehydrogenase - genetics; Life Sciences; Male; Medical research; Medical schools; Medicine; Medicine & Public Health; Methylation; Neoplasm Grading; Neurosciences; Original Paper; Pathology; Preservation; Progression-Free Survival; Promoter Regions, Genetic; Quality of life; Radiation therapy; Radiotherapy; Survival; Temozolomide; Temozolomide - therapeutic use; Treatment Outcome; Tumor Suppressor Proteins; Tumor Suppressor Proteins - genetics
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-018-1810-6

The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We first identified 62 functionally relevant CpG sites located in the promoters of 24 DDR genes, using the LGG data from The Cancer Genome Atlas. Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG. The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT , MLH3 , RAD21 , and SMC4 . Most interestingly, the two CpGs identified for MGMT are the same, previously selected for the MGMT-STP27 score that is used to determine the methylation status of the MGMT gene. This score was higher in the LGG with 1p/19q codeletion, in this and other independent LGG datasets. It was predictive for PFS in the TMZ, but not in the RT arm of EORTC 22033. The results support the hypothesis that a high score predicts benefit from TMZ treatment for patients with IDHmt LGG, regardless of the 1p/19q status. This MGMT methylation score may identify patients who benefit from first-line treatment with TMZ, to defer RT for long-term preservation of cognitive function and quality of life.