Epigenetic evolution of IDHwt glioblastomas

We generated whole genome DNA methylation data of 64 matched primary-recurrent samples from IDH-wildtype glioblastoma patients. Data were combined with three publicly available datasets into a final cohort consisting of 418 samples. In the combined dataset, we determined change in genome-wide DNA-methylation.

MGMT promoter methylation was defined using the MGMT-STP27 algorithm. CoxPH regression was used to investigate the impact of identified changes on survival. Results Our analysis demonstrates that the methylome of IDH-wildtype glioblastomas is highly stable.

Changes that do occur can mostly be allocated to differences in tumor purity. Conversion from a MGMT promoter methylated to unmethylated status at progression occurred infrequently, but significantly more often than the converse. Conversion was associated with poorer overall and progression-free survival compared to those that remained MGMT methylated.

Similar to previously reported, MGMT promoter methylation status was significantly associated with overall-, progression-free and post-recurrence survival. Despite this large survival difference, very few CpGs were co-methylated with the MGMT methylation status. Of these, the vast majority lied within the MGMT gene body and were inversely correlated with MGMT promoter methylation status.

Conclusions The methylome of IDH-wildtype glioblastomas is highly stable at tumor progression. This stability is also present in the MGMT promoter.