Methylation Patterns of Oligodendroglial Tumors
Barbara Melendez, Pilar Mur, Manuela Mollejo, Concepcion Fiano, Juan F Garcia, Aurelio Hernandez Lain, Angel Rodriguez de Lope, Juan A Rey. Virgen de la Salud Hospital, Toledo, Spain; Xeral-Cíes Hospital, Vigo, Spain; MD Anderson International, Madrid, Spain; 12 de Octubre Hospital, Madrid, Spain; Puerta de Hierro Hospital, Madrid, Spain; La Paz Hospital, Madrid, Spain
Background: Oligodendroglial tumors (OTs) present a variable biological behaviour depending on the presence of 1p/19q deletion and IDH mutation. Combined 1p/19q loss occurs in oligodendrogliomas and mixed oligoastrocitomas. The presence of this deletion involves better prognosis and treatment response. A prognostically favorable CpG island methylation phenotype was reported in gliomas (G-CIMP+). Recently, G-CIMP+ tumors have been associated to IDH mutations. The major goal of this study was to analyze the methylation status of the whole genome in OTs.
Design: We included 46 high and low grade OTs (34 oligodendrogliomas and 12 oligoastrocytomas), and 5 non-tumoral brain samples as controls. Whole genome methylation profiling analyses were performed (450K, Illumina). Our results were validated by using external datasources. Tumors were characterized for 1p/19q codeletion by FISH or LOH, and for IDH mutation by direct sequencing.
Results: The G-CIMP+ phenotype was strongly associated to IDH mutation and to combined 1p/19q loss, while G-CIMP- tumors did not show either IDH mutation or 1p/19q codeletion. Furthermore, G-CIMP+ tumors could be separated into two groups according to the different methylation profile: i) tumors G-CIMP+, which showed IDH mutation and 1p/19q codeletion; and ii) tumors showing an intermediate methylation profile (G-CIMP+/-), featured by IDH mutation and absence of 1p/19q codeletion. These different G-CIMP profiles did not correlate with tumoral grade or subtype. Methylation data from glioblastomas (TCGA database) showed that most of primary GBMs were G-CIMP-, while a few of them presented a G-CIMP+/- profile. Striking differences on overall survival times (P<0.01) were observed between G-CIMP- and either G-CIMP+ or G-CIMP+/-, which could be due to lack of good prognostic molecular features of G-CIMP- tumors. A non-significant tendency toward a better overall survival of G-CIMP+ tumors compared to G-CIMP+/- is also observed.
Conclusions: This study allowed us to classify OTs according to their methylation profiles, which were related to the IDH and 1p/19q status, but were independent of the tumoral grade or subtype. Higher levels of aberrant methylation (CIMP+) were identified in IDH mutated, 1p/19q deleted tumors. Intermediate methylation profiles were observed in IDH mutated tumors with intact 1p/19q. The G-CIMP status could have an important impact on survival.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 230, Tuesday Morning