Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups.

Abstract

Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.

• Authors: Michael Weller, Ruthild G Weber, Edith Willscher, Vera Riehmer, Bettina Hentschel, Markus Kreuz, Jörg Felsberg, Ulrike Beyer, Henry Löffler-Wirth, Kerstin Kaulich, Joachim P Steinbach, Christian Hartmann, Dorothee Gramatzki, Johannes Schramm, Manfred Westphal, Gabriele Schackert, Matthias Simon, Tobias Martens, Jan Boström, Christian Hagel, Michael Sabel, Dietmar Krex, Jörg C Tonn, Wolfgang Wick, Susan Noell, Uwe Schlegel, Bernhard Radlwimmer, Torsten Pietsch, Markus Loeffler, Andreas von Deimling, Hans Binder, Guido Reifenberger
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 129 Issue 5 Pg. 679-93 (May 2015) ISSN: 1432-0533 [Electronic] Germany
• PMID: 25783747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Brain Neoplasms (genetics)
• Female
• Gene Expression Profiling (methods)
• Genomics (methods)
• Glioma (classification, genetics, pathology, physiopathology)
• Humans
• Isocitrate Dehydrogenase (genetics)
• Male
• Middle Aged
• Mutation
• Neoplasm Grading (methods)
• Prognosis
• Promoter Regions, Genetic
• Sequence Deletion
• World Health Organization
• Young Adult