Abstract 3093: Unravelling the biology of aggressive and therapy-resistant embryonal tumors with multilayered rosettes (ETMR)
Authors: Kool Marcel , Jäger Natalie , Sturm Dominik , Jones David T.W. , Hoverstadt Volker , Buchhalter Ivo , Johann Pascal , Schmidt Christin , Ryzhova Marina , Northcott Paul A. , Landgraf Pablo , Remke Marc , Taylor Michael D. , Hasselblatt Martin , Schüller Ulrich , Huang Annie , Yaspo Marie-Laure , Deimling Andreas von , Eils Roland , Lichter Peter , Korshunov Andrey , Pfister Stefan M. 
Published: May 2015

Abstract
Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive embryonal CNS tumor, which predominantly affects children under the age of three to four years and is associated with a highly aggressive disease course with reported overall survival times ranging from 5-30 months. As these tumors have often been misdiagnosed as medulloblastoma or CNS-PNETs it was thought that ETMR is a very rare tumor. However, now molecular tools are available to detect ETMR and distinguish them from other brain tumors it has become clear that it is one of the most common brain tumors among infants. Amplification of a miRNA cluster at 19q13.42 and high expression of LIN28A have been identified as molecular hallmarks of ETMR, affecting 95-100% of samples tested and are considered unifying molecular diagnostic markers to detect them and distinguish from other brain tumors. Three histological variants of ETMR are known. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). A comprehensive clinical, pathological, and molecular analysis of 97 cases of these fatal brain neoplasms identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. In particular, DNA methylation (Illumina 450k arrays) and gene expression data (Affymetrix 133plus2.0 arrays) showed that the three histological variants of ETMR are biologically indistinguishable but together highly distinct from other pediatric brain tumors. In order to better understand the biology of these highly aggressive pediatric CNS malignancies, we performed whole genome DNA sequencing of 15 tumor-normal pairs including 3 recurrences, complemented by (mi)RNA sequencing of tumor RNA. Mutations detected included mutations in TP53, CTNNB1, and mutations affecting the miRNA processing pathway. Chromothripsis was detected in several cases and in all cases affecting chromosome 19q. Finally, as DNA sequencing identified only very few somatic mutations per tumor, we next studied the epigenome of these tumors by performing whole genome bisulfite sequencing. Integrating these high throughput genomic analyses may now lead to alternative treatment strategies for these highly aggressive and therapy-resistant tumors.
Citation Format: Marcel Kool, Natalie Jäger, Dominik Sturm, David T.W. Jones, Volker Hoverstadt, Ivo Buchhalter, Pascal Johann, Christin Schmidt, Marina Ryzhova, Paul A. Northcott, Pablo Landgraf, Marc Remke, Michael D. Taylor, Martin Hasselblatt, Ulrich Schüller, Annie Huang, Marie-Laure Yaspo, Andreas von Deimling, Roland Eils, Peter Lichter, Andrey Korshunov, Stefan M. Pfister. Unravelling the biology of aggressive and therapy-resistant embryonal tumors with multilayered rosettes (ETMR). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3093. doi:10.1158/1538-7445.AM2014-3093