Abstract
BACKGROUND: Glioblastoma (GB) is the most frequent and lethal form of diffuse glioma. GB displays chromosome instability and recurrent somatic copy number alterations. Recently, chromothripsis (CT) has been identified in cancer patients. It is a cataclysmic event in which a single or a few chromosomes (chr) are shattered and then randomly reassembled in a derivative chr, sometimes with additional double-minute chr and gene amplification. It may also disrupt tumor suppressor genes or lead to oncogenic fusion genes. Such genes may represent potential therapeutic targets. CT and consequent gene fusions have not been well described in large GB cohorts. METHODS: We used pan-genomic single nucleotide polymorphism (SNP) arrays (CytoSNP 850K, Illumina) to identify CT patterns in 183 primary GB. We performed RNA sequencing in 19 cases with CT. We validated the gene fusions detected by RT-PCR and Sanger sequencing. RESULTS: CT occurred in 38.3 % of GB (70/183 cases) and mostly affected chrs 7, 9 and 12, with amplification of oncogenes (e.g., EGFR, MDM2/CDK4), and homozygous deletion of tumor suppressor genes (e.g., CDKN2A). We detected and validated 26 gene fusions (17 in-frame and 9 out-of-frame) in 15 of the 19 cases RNA-sequenced. The 17 in-frame fusions (from 11 patients) were all located in CT regions. They were intrachromosomal events involving nearby genes. We identified novel gene fusions implicating (potential) oncogenes such as ACVR1, MDM2, HMGA2, EGFR, MET, and MAPK4. Some of these fusions may be recurring events like the FGFR3-TACC3 fusion. Additional GB cases with CT are being RNA-sequenced. CONCLUSION: CT is a frequent event in GB. It recurrently targets key genes in gliomagenesis/tumor progression and leads to gene fusions in GB. Thorough analysis of genomic regions affected by CT will most likely lead to the identification of novel fusion genes, potential therapeutic targets in this fatal disease.