A Hypermethylated Phenotype Is a Better Predictor of Survival than MGMT Methylation in Anaplastic Oligodendroglial Brain Tumors: A Report from EORTC Study 26951

Abstract

Purpose: The MGMT promoter methylation status has been suggested to be predictive for outcome to temozolomide chemotherapy in patients with glioblastoma (GBM). Subsequent studies indicated that MGMT promoter methylation is a prognostic marker even in patients treated with radiotherapy alone, both in GBMs and in grade III gliomas.Experimental Design: To help determine the molecular mechanism behind this prognostic effect, we have conducted genome-wide methylation profiling and determined the MGMT promoter methylation status, 1p19q LOH, IDH1 mutation status, and expression profile on a series of oligodendroglial tumors [anaplastic oligodendrogliomas (AOD) and anaplastic oligoastrocytomas (AOA)] within EORTC study 26951. The series was expanded with tumors of the same histology and treatment from our own archive.Results: Methylation profiling identified two main subgroups of oligodendroglial brain tumors of which survival in the CpG island hypermethylation phenotype (CIMP þ ) subgroup was markedly better than the survival of the unmethylated (CIMP À ) subgroup (5.62 vs. 1.24 years; P < 0.0001). CIMP status correlated with survival, MGMT promoter methylation, 1p19q LOH, and IDH1 mutation status. CIMP status strongly increases the predictive accuracy of survival in a model including known clinical prognostic factors such as age and performance score. We validated our results on an independent data set from the Cancer Genome Atlas (TCGA).Conclusion: The strong association between CIMP status and MGMT promoter methylation suggests that the MGMT promoter methylation status is part of a more general, prognostically favorable genome-wide methylation profile. Methylation profiling therefore may help identify AODs and AOAs with improved prognosis. Clin Cancer Res; 17(22); 7148-55. Ó2011 AACR.

MGMT-STP27 Methylation Status as Predictive Marker for Response to PCV in Anaplastic Oligodendrogliomas and Oligoastrocytomas. A Report from EORTC Study 26951

“…Similar to other studies, we found a strong correlation between a genome-wide hypermethylation phenotype ("CIMP") and survival (8)(9)(10)(11). However, preliminary analysis also indicated that CIMP status may be predictive for response to PCV chemotherapy.…”

“…Bisulfite-converted DNA was then hybridized to Illumina Infinium HumanMethylation 27 arrays (Illumina) by Service XS or to Infinium HumanMethylation 450 arrays (Illumina) run by ArosAB according to standard Illumina protocols. Data from 50 Infinium HumanMethylation 27 arrays samples were previously reported (11). All array data is available via the NCBI GEO datasets, accession number GSE48462.…”

“…Of these, 8 were FF and run on HumanMethylation27 beadchips, 59 were FFPE and run on HumanMethylation450 beadchips. Data were combined with 50 samples that were analyzed previously using FF samples on HumanMethylation27 beadchips (11). Data are available via NCBI GEO datasets, GSE48462.…”

The CpG Island Methylator Phenotype: What's in a Name?

“…For instance, B-CIMP tumors were associated with ESR1/PGR status, a lower risk of metastasis, and an improved clinical outcome (10). G-CIMP has been associated with improved survival, younger age at diagnosis, and histologic characteristics (20,22). Furthermore, using the Infinium array, a recent methylome analysis in a study of patients with primary clear cell renal carcinoma showed that CIMP characterized a specific cluster of tumors associated with aggressiveness and patient outcome (32).…”

“…[20][21][22], hepatocellular (23)(24)(25)(26), lung (27,28), ovarian (29), pancreatic (30), prostate (31), and renal cell (32) cancers, as well as in leukemia (33)(34)(35)(36), melanoma (37), duodenal adenocarninomas (38), adrenocortical carcinomas (39), and neuroblastomas (40,41). The primary purpose of these studies was to determine if CIMP is also present in these cancers, and if it can be used to distinguish between known phenotypes of the respective cancer type.…”