The tumoral molecular landscape of long-term survivors with isocitrate dehydrogenase wildtype glioblastoma: Lessons from ETERNITY (EORTC 1419).

Abstract

2059 Background: Predictors of long-term survival in patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma remain incompletely understood. ETERNITY (EORTC 1419) is the largest registry study of glioblastoma patients surviving for 5 years or more worldwide. Methods: Here we characterized the DNA methylation and mutational landscapes of 142 tumors from ETERNITY patients and compared the findings with different reference cohorts. Results: The majority of tumors of the ETERNITY cohort showed molecular profiles corresponding to established methylation subclasses of IDH-wildtype glioblastoma. ETERNITY tumors were enriched for the mesenchymal subclass, depleted of the receptor tyrosine kinase 1 subclass, and showed a high frequency of MGMT promoter methylation. While large chromosomal alterations were remarkably similar in all cohorts, circumscribed homozygous deletions on chromosome 10q including the MGMT gene were enriched in ETERNITY tumors. Gene panel sequencing showed similar types and frequencies of gene alterations as in the reference cohorts with a trend towards more frequent RB1 mutations. Deconvolution analyses of global DNA methylation data revealed fewer monocytes in the MES methylation class in ETERNITY compared with the reference cohort. ETERNITY tumors from patients without documented relapse showed no specific molecular profile. Small subgroups of tumors corresponded to rare incompletely defined tumor entities. Conclusions: The present study illustrates the profound association of MGMT gene alterations with outcome, but also suggests as yet unidentified clinical or molecular pathways and potential host-dependent features in long-term survival with glioblastoma. Clinical trial information: NCT03770468 .