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

Abstract

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.

Identification of candidate target genes of genomic aberrations in esophageal squamous cell carcinoma

“…Differentially expressed genes associated with DNA copy number changes may be candidate targets of amplifications or homozygous deletions, and play significant roles in tumorigenesis and the development of cancer (8). 9p21.3 is the most common loss in numerous types of cancer, including glioblastoma, esophageal cancer and pancreatic cancer (9,10), and is also the most frequent early event in the tumorigenesis of Epstein-Barr virus-associated nasopharyngeal carcinoma (11). CDKN2A and CDKN2B were identified as the driver genes of 9p21.3 loss.…”

Limited role for extended maintenance temozolomide for newly diagnosed glioblastoma

“…Treatment decisions were made by the treating physicians, patients, and their families, commonly without awareness of the MGMT promoter methylation status; 35 patients were included in previous publications. 16,[19][20][21][22][23][24][25] MRI scans or at least written reports were collected at the time point when 6 cycles of TMZ chemotherapy were completed to assess tumor status. MRI scans of 36 patients were available for central radiology assessment (P.K., M.B.)…”

Perspectives and Challenges in Molecular-Based Diagnostics and Personalized Treatment for Recurrent High-Grade Gliomas

“…As a consequence of such treatment-driven and molecular type-dependent evolution, recGBs may considerably deviate in their molecular landscapes from precursor tumors. In agreement with this hypothesis, comparative profiling has revealed considerable differences between ndGBs and recGBs in mutational spectrum, frequency of genomic rearrangemens and gene expression patterns [29,30]. Notably, a considerable number of fusion transcripts identified in recGBs involve genes that have not previously been associated with gliomas suggesting that therapeutically actionable lesions in recGBs may differ from those identified in ndGBs.…”

“…In the study by Riemer and co-authors more than 40% of recGBs showed genomic aberration patterns distinct from those in their ndGBs counterparts [30]. Based on the degree of (dis)similarity with the patterns of genomic aberrations characteristic of ndGBs, recGBs could be stratified into distinct molecular types termed "equal", "sequential" or "discrepant" [30]. The existence of genetically distinct subgroups across recGBs further indicates that recGBs are molecularly heterogeneous tumours that may evolve through clonal selection proactively enforced by cytotoxic treatments.…”

“…Notably, a considerable number of fusion transcripts identified in recGBs involve genes that have not previously been associated with gliomas suggesting that therapeutically actionable lesions in recGBs may differ from those identified in ndGBs. In the study by Riemer and co-authors more than 40% of recGBs showed genomic aberration patterns distinct from those in their ndGBs counterparts [30]. Based on the degree of (dis)similarity with the patterns of genomic aberrations characteristic of ndGBs, recGBs could be stratified into distinct molecular types termed "equal", "sequential" or "discrepant" [30].…”