Methylome analysis for prediction of long and short-term survival in glioblastoma patients from the Nordic trial

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Abstract
Patients with glioblastoma (GBM) have a short survival, but even among patients receiving the same therapies and with good prognostic factors, one can find those with exceptionally short and long survival. In the Nordic trial, patients with GBM, 60 years or older, were randomized between 2 radiotherapy arms or TMZ. We selected 59 patients, equally distributed between the 3 treatment arms and MGMT promoter methylation status, with good prognostic factors, but with short or long survival. We performed methylation profiling with the Illumina Infinium Methylation EPIC BeadChip arrays in conjunction with a methylation-based CNS tumor classifier, analysis of differentially methylated CpG sites (DMCs) and pathway enrichment analysis. Samples classified as non-GBM IDH wildtype were excluded and in the analysis of long vs. short survivors with documented progression or tumor-related death, we found DMCs in the TMZ, MGMT promoter methylated group (123,510), as well as in the 60Gy, MGMT promoter unmethylated group (4,086) and 34Gy, MGMT promoter methylated group (39,649). The joint analysis of the RT arms revealed 319 DMCs in the MGMT unmethylated group but no differences for MGMT promoter methylated samples, or in any of the analyses independent of MGMT status. Interestingly, in the long-term survivors with methylated MGMT promoter treated with TMZ we found hypermethylation of the Wnt signaling and the platelet activation, signaling and aggregation pathways. We identified DMCs for both TMZ and RT treated patients. Further systematic analysis of larger patient cohorts is necessary for confirmation of their predictive properties.
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