Translocations and catastrophe – chromothriptic disruption of transcription factors in ependymoma


Session type:

Richard Gilbertson1
1Cancer Research UK Cambridge Institute


Whole genome sequencing of ependymoma – the third most common brain tumour of childhood – has revealed structural and copy number changes at the chromosomal level, but very few focal alterations of specific genes. These non-random chromosome copy number alterations are large, making it difficult to pinpoint which genes are driving the cancer. This talk describes two approaches to unmask specific genes that drive ependymoma. First, we used a cross-species in vivo screen of 84 candidate oncogenes and 39 candidate tumour suppressor genes, located within recurrent chromosomal alterations to validate eight new ependymoma oncogenes and ten new ependymoma tumour suppressor genes. Second, we show that chromothripsis underpins a series of highly recurrent oncogenic fusions between RELA, the principal effector of canonical NFkB signalling, and an uncharacterised gene, C11orf95 in more than two-thirds of supratentorial ependymomas. Together, these data reveal the importance of large chromosomal alterations in driving paediatric ependymoma; mechanisms to identify the genes that are targeted by these events; and thereby potential new therapeutic approaches.