Abstract 3687: An integrative genomics approach identifies distinct molecular and epigenetic subgroups of pediatric glioblastoma
Authors: Sturm Dominik , Witt Hendrik , Jacob Karine , Konermann Carolin , Jones David TW , Pfaff Elke , Korshunov Andrey , Rizhova Marina , Hovestadt Volker , Remke Marc , van Meter Timothy , Frühwald Michael , Kramm Christoph , Kulozik Andreas E. , von Deimling Andreas , Hartmann Christian , Milde Till , Witt Olaf , Reifenberger Guido , Lichter Peter , Plass Christoph , Jabado Nada , Pfister Stefan M. 
Published: August 2012

Abstract
Pediatric glioblastoma (GBM) belongs to the comparably small group of childhood malignancies for which cure is still an exception. Histologically indistinguishable from their adult counterparts, they carry a similar dismal prognosis. Whereas genetic and epigenetic properties have been extensively studied in adult tumors, little is known about the molecular characteristics of pediatric GBM, although some reports indicate that it is likely a different entity in terms of tumor biology and molecular genetics. Thus, this study aimed to elucidate disease-defining molecular lesions by determining genomic, transcriptomic and epigenetic alteration profiles. Using an integrative genomics approach combining multiple screening strategies, we investigated primary tumor samples from 55 childhood GBM for copy-number aberrations (CNA), transcriptomic and epigenetic changes, complemented by sequencing analysis of TP53, IDH1/2 and further candidate genes. Methylome analysis revealed the existence of five separate clusters of childhood GBM with distinct molecular and clinico-pathological features. Methylation patterns correlated with novel recurrent, subgroup-specific driver mutations unique to the pediatric population, and with clearly distinguishable transcriptomic profiles. Integration of methylation and gene expression data suggested that different tumor subgroups are derived from at least two distinct precursor-cell populations, one of them without any signs of neural lineage commitment. Furthermore, distinct clusters were highly associated with the presence of balanced (13%) or aneuploid (33%) genomic profiles or with cases displaying highly-rearranged genomes (11%), or various high-level focal amplifications (43%) of known and novel oncogenes. Similar to adults, CNA frequently targeted GBM core signaling pathways such as RTK/PI3K, p53 and RB signaling. TP53 loss-of-function mutations were present in 46% of pediatric GBM. IDH1 mutations were detected in only six patients (11%), but these tumors displayed concerted hypermethylation at a large number of loci, resembling a CpG island methylator phenotype (CIMP). Relevant findings are being validated by immunohistochemistry or FISH analysis in an independent, large-scale cohort representing 130 uniformly-treated pediatric GBM. This study, one of the largest cohorts of pediatric GBM investigated for molecular alterations to date, describes frequent genetic and epigenetic features of this devastating disease and further emphasizes and differences between adult and pediatric GBM. The identification of distinct molecular subgroups and commonly altered pathways will help to characterize molecular biomarkers for improved prognostic assessment and risk-adapted treatment stratification, and may facilitate the development of suitable in vitro and in vivo models for defining novel therapeutic strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3687. doi:1538-7445.AM2012-3687