ABSTRACT
Cancers are characterized by non-random chromosome copy number alterations that presumably contain oncogenes and tumor-suppressor genes (TSGs). The affected loci are often large, making it difficult to pinpoint which genes are driving the cancer. Here we report a cross-species in vivo screen of 84 candidate oncogenes and 39 candidate TSGs, located within 28 recurrent chromosomal alterations in ependymoma. Through a series of mouse models, we validate eight new ependymoma oncogenes and ten new ependymoma TSGs that converge on a small number of cell functions, including vesicle trafficking, DNA modification and cholesterol biosynthesis, identifying these as potential new therapeutic targets.
Subject(s)
Ependymoma/genetics , Genes, Tumor Suppressor , Genetic Predisposition to Disease/genetics , Oncogenes/genetics , Animals , Cells, Cultured , Chromosome Aberrations , DNA Copy Number Variations , Ependymoma/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , Kaplan-Meier Estimate , Male , Mice, Nude , Mice, Transgenic , Microscopy, Confocal , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Neural Stem Cells/metabolism , Neural Stem Cells/transplantation , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction , TransfectionABSTRACT
Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells--the cell of origin of ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.
Subject(s)
Cell Transformation, Neoplastic , Ependymoma/genetics , Ependymoma/metabolism , NF-kappa B/metabolism , Proteins/metabolism , Signal Transduction , Transcription Factor RelA/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Base Sequence , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Line , Cell Nucleus/metabolism , Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 11/genetics , Ependymoma/pathology , Female , Humans , Mice , Models, Genetic , Molecular Sequence Data , NF-kappa B/genetics , Neural Stem Cells/metabolism , Neural Stem Cells/pathology , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Proteins/genetics , Transcription Factor RelA/genetics , Transcription Factors , Translocation, Genetic/genetics , YAP-Signaling ProteinsABSTRACT
Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.
