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Genomic profiling reveals distinctive molecular relapse patterns in IDH1/2 wild‐type glioblastoma
Author(s) -
Riehmer Vera,
Gietzelt Jens,
Beyer Ulrike,
Hentschel Bettina,
Westphal Manfred,
Schackert Gabriele,
Sabel Michael C.,
Radlwimmer Bernhard,
Pietsch Torsten,
Reifenberger Guido,
Weller Michael,
Weber Ruthild G.,
Loeffler Markus
Publication year - 2014
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22169
Subject(s) - cdkn2a , biology , comparative genomic hybridization , idh1 , somatic evolution in cancer , locus (genetics) , gene , cancer research , tumor progression , copy number variation , primary tumor , genome , genetics , glioblastoma , gene dosage , cancer , mutant , gene expression , metastasis
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.