Genomic profiling reveals distinctive molecular relapse patterns in IDH1/2 wild-type glioblastoma.

Molecular changes associated with the progression of glioblastoma after standard radiochemotherapy remain poorly understood. We compared genomic profiles of 27 paired primary and recurrent IDH1/2 wild-type glioblastomas by genome-wide array-based comparative genomic hybridization. By bioinformatic analysis, primary and recurrent tumor profiles were normalized and segmented, chromosomal gains and losses identified taking the tumor cell content into account, and difference profiles deduced. Seven of 27 (26%) pairs lacked DNA copy number differences between primary and recurrent tumors (equal pairs). The recurrent tumors in 9/27 (33%) pairs contained all chromosomal imbalances of the primary tumors plus additional ones, suggesting a sequential acquisition of and/or selection for aberrations during progression (sequential pairs). In 11/27 (41%) pairs, the profiles of primary and recurrent tumors were divergent, i.e., the recurrent tumors contained additional aberrations but had lost others, suggesting a polyclonal composition of the primary tumors and considerable clonal evolution (discrepant pairs). Losses on 9p21.3 harboring the CDKN2A/B locus were significantly more common in primary tumors from sequential and discrepant (nonequal) pairs. Nonequal pairs showed ten regions of recurrent genomic differences between primary and recurrent tumors harboring 46 candidate genes associated with tumor recurrence. In particular, copy numbers of genes encoding apoptosis regulators were frequently changed at progression. In summary, approximately 25% of IDH1/2 wild-type glioblastoma pairs have stable genomic imbalances. In contrast, approximately 75% of IDH1/2 wild-type glioblastomas undergo further genomic aberrations and alter their clonal composition upon recurrence impacting their genomic profile, a process possibly facilitated by 9p21.3 loss in the primary tumor. © 2014 Wiley Periodicals, Inc.

Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling.

The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.