Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951

Ahmed Idbaih, Cyril Dalmasso, Mathilde Kouwenhoven, Judith Jeuken, Catherine Carpentier, Thierry Gorlia, Johan M Kros, Pim French, Johannes Teepen, Philippe Broët, Olivier Delattre, Karima Mokhtari, Marc Sanson, Jean-Yves Delattre, Martin van den Bent, Khê Hoang-Xuan, Ahmed Idbaih, Cyril Dalmasso, Mathilde Kouwenhoven, Judith Jeuken, Catherine Carpentier, Thierry Gorlia, Johan M Kros, Pim French, Johannes Teepen, Philippe Broët, Olivier Delattre, Karima Mokhtari, Marc Sanson, Jean-Yves Delattre, Martin van den Bent, Khê Hoang-Xuan

Abstract

Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify new genomic regions associated with prognosis, 60 AOTs from the EORTC trial 26951 were analyzed retrospectively using BAC-array-based comparative genomic hybridization. The data were processed using a binary tree method. Thirty-three BACs with prognostic value were identified distinguishing four genomic subgroups of AOTs with different prognosis (p < 0.0001). Type I tumors (25%) were characterized by: (1) an EGFR amplification, (2) a poor prognosis, (3) a higher rate of necrosis, and (4) an older age of patients. Type II tumors (21.7%) had: (1) loss of prognostic BACs located on 1p tightly associated with 19q deletion, (2) a longer survival, (3) an oligodendroglioma phenotype, and (4) a frontal location in brain. Type III AOTs (11.7%) exhibited: (1) a deletion of prognostic BACs located on 21q, and (2) a short survival. Finally, type IV tumors (41.7%) had different genomic patterns and prognosis than type I, II and III AOTs. Multivariate analysis showed that genomic type provides additional prognostic data to clinical, imaging and pathological features. Similar results were obtained in the cohort of 45 centrally reviewed-validated cases of AOTs. Whole genome analysis appears useful to screen the numerous genomic abnormalities observed in AOTs and to propose new biomarkers particularly in the non-1p/19q codeleted AOTs.

Figures

Fig. 1
Fig. 1
Frequencies of genomic abnormalities in the entire population of anaplastic oligodendroglial tumors. The x-axis indicates the BACs and chromosome arms along the genome while the y-axis indicates the frequency of genomic alterations with genomic losses on the bottom (gray histograms) and genomic gains on top (black histograms)
Fig. 2
Fig. 2
Genetic-prognostic tree built from the 33 relevant genetic-prognostic BACs
Fig. 3
Fig. 3
Chromosome location of the 33 BACs with prognostic value identified as relevant to build the genetic-prognostic tree (see Supplementary Table 4 for the full-length name and genomic position of BACs reported in this figure). a, b and c indicate chromosomes 1, 7 and 21, respectively. Along the vertical axis, each dot represents a BAC. The horizontal axis indicates chromosome distance from the telomere (d) of BACs with prognostic value identified in each chromosome. Broken arrow indicates chromosome centromere
Fig. 4
Fig. 4
Overall survival of anaplastic oligodendroglial tumors (AOT) patients according to the genetic-prognostic type of their tumor based on the initial diagnosis of AOT (a) and the centrally reviewed-validated diagnosis of AOT (b). Kaplan–Meier curves with x-axis and y-axis indicating the overall survival in years and the percentage of survivors, respectively. Thick continuous line, thin continuous line, thick broken line and thin broken line indicate type II, type IV, type III and type I tumors patients, respectively

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