Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 601-615 |
| Number of pages | 15 |
| Journal | Acta Neuropathologica |
| Volume | 135 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2018 |
Funding
Acknowledgements The authors would like to thank the staff at the participating centers of EORTC 22033, the EORTC Headquarter and the German Glioma Network for their great support as well as the participating patients and their relatives. The results published here are in part based upon data generated by The Cancer TCGA Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions constituting the TCGA research network can be found at “http://cancergenome.nih.gov”. This work was supported by the Swiss Bridge Award 2011, the Swiss Cancer League (KFS-29-02-2012 to MEH) and the Swiss National Science Foundation (3100A-163297, to MEH and MD). The authors would like to thank the staff at the participating centers of EORTC 22033, the EORTC Headquarter and the German Glioma Network for their great support as well as the participating patients and their relatives. The results published here are in part based upon data generated by The Cancer TCGA Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions constituting the TCGA research network can be found at ?http://cancergenome.nih.gov ?. This work was supported by the Swiss Bridge Award 2011, the Swiss Cancer League (KFS-29-02-2012 to MEH) and the Swiss National Science Foundation (3100A-163297, to MEH and MD). MJvdB has received grants from Roche and Abbvie, and personal fees from Roche, Abbvie, Merck AG, Novocure, Cavion, Bristol-Myers Squibb, Novartis, and Actelion. BT acknowledges financial support from NCIC-CTG, during the conduct of the study. OC reports grants, personal fees and non-financial support from Roche, and personal fees from Ipsen and AstraZeneca. MJBT reports personal fees from Hoffmann La Roche. W.W. has participated in a speaker?s bureau for and has received research funding from MSD, received research funding from Apogenix, Boehringer Ingelheim, Genentech Roche and Pfizer, has a consultant relationship with BMS, Celldex and Genentech/Roche. AvD reports a patent (US 8,367,347 B2) with royalties paid to Dianova GmbH (Hamburg, Germany). RS received non-financial support from Novocure; his institution received honoraria from Roche, Merck KGaA, MSD, Merck, and Novartis. BGB reports personal fees from Merck Sharp & Dohme (MSD). MEH has received grants from Orion, service fees from Novocure, and has served on advisory board from BMS, and received non-financial support from MDxHealth. Funding This work was supported by the Swiss Bridge Award 2011, the Swiss Cancer League (KFS-29-02-2012 to MEH) and the Swiss National Science Foundation (3100A-163297, to MEH and MD).
Keywords
- DDR genes
- DNA methylation
- Low-grade glioma
- MGMT-STP27
- Randomized trial
- TMZ
ASJC Scopus subject areas
- Clinical Neurology
- Cellular and Molecular Neuroscience
- Pathology and Forensic Medicine
