Abstract 2793: A hypermethylated phenotype in anaplastic oligodendroglial brain tumors is a better predictor of survival than MGMT methylation in the EORTC 26951 study

Abstract

Abstract We have performed methylation profiling (Illumina Human Methylation 27 beadchip) on 69 anaplastic oligodendrogliomas (AOD) or anaplastic mixed oligoastrocytomas (MOA) and one non-diseased normal brain. Fifty-two of these samples were treated as part of the EORTC 26951 study, the primary objective of which was to compare the overall survival (OS) of patients with AOD or MOA treated with radiotherapy (59.4 Gy) vs. ± PCV chemotherapy. Remaining samples were also AOD or MOA and received similar treatment paradigms. Unsupervised clustering using hierarchical ordered partitioning and collapsing hybrid (Hopach) was performed using all or the 10,000, 5,000, 2,000, 1,000, 500, 200 or 100 most variably methylated CpG loci. In all analyses, we identified two main clusters that were highly stable (determined by Fuzzy clustering). In general, these clusters could be separated by predominantly methylated vs. unmethylated CpG loci. Survival (as determined from the date of resection) in the “hypermethylated” subgroup was markedly better than the survival of the unmethylated subgroup (5. 62 vs. 1.24 years, P<0.0001). In fact, methylation profiling was able to better separate long vs. short survivors than histology, MGMT promoter methylation status (as determined by MLPA), 1p/19q LOH (as determined by FISH) or IDH1 mutation status. Methylation phenotype remained an independent prognostic marker in a multivariate analysis that includes diagnosis, age, sex, 1p19q LOH and IDH1 mutation status. We validated our results on methylation profiling data from the cancer genome atlas (TCGA) by assigning TCGA samples to one of the molecular clusters identified in our dataset. 14/80 and 66/80 samples of were assigned to the “hypermethylated” and “unmethylated” cluster respectively. Similar to the initial “test” dataset, survival between the hypermethylated and unmethylated subgroups were significantly different (2.87 vs. 1.02 years, P<0.0001). In conclusion, methylation profiling has identified two main subgroups of oligodendroglial brain tumors. These methylation subgroups correlate better with survival than histology, MGMT promoter methylation, 1p19q LOH and IDH1 mutation status. We are currently integrating methylation data with expression data. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2793. doi:10.1158/1538-7445.AM2011-2793