A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival

Abstract

With the advent of high-throughput sequencing technologies, much progress has been made in the identification of somatic structural rearrangements in cancer genomes. However, characterization of the complex alterations and their associated mechanisms remains inadequate. Here, we report a comprehensive analysis of whole-genome sequencing and DNA copy number data sets from The Cancer Genome Atlas to relate chromosomal alterations to imbalances in DNA dosage and describe the landscape of intragenic breakpoints in glioblastoma multiforme (GBM). Gene length, guanine–cytosine (GC) content, and local presence of a copy number alteration were closely associated with breakpoint susceptibility. A dense pattern of repeated focal amplifications involving the murine double minute 2 (MDM2)/cyclin-dependent kinase 4 (CDK4) oncogenes and associated with poor survival was identified in 5% of GBMs. Gene fusions and rearrangements were detected concomitant within the breakpoint-enriched region. At the gene level, we noted recurrent breakpoints in genes such as apoptosis regulator FAF1. Structural alterations of the FAF1 gene disrupted expression and led to protein depletion. Restoration of the FAF1 protein in glioma cell lines significantly increased the FAS-mediated apoptosis response. Our study uncovered a previously underappreciated genomic mechanism of gene deregulation that can confer growth advantages on tumor cells and may generate cancer-specific vulnerabilities in subsets of GBM.

The proteomic landscape of glioma stem-like cells

“…In addition, our results for affected biochemical pathways are consistent with those which have been previously reported. For instance, glycolysis and gluconeogenesis have been shown to be upregulated in mesenchymal GSCs [54]. Confirmation of known findings gives greater confidence in the novel findings in our dataset, which may be used as a basis for further mechanistic studies into GBM chemoresistance.…”

Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution

“…Genomic studies have further illustrated this disease characteristic by demonstrating local variation in the amplification patterns of receptor tyrosine kinases (Snuderl et al 2011;Szerlip et al 2012;Sottoriva et al 2013;Francis et al 2014) as well as a wide landscape of somatic alterations, expression subtypes, and epigenetic differences across GBM (Noushmehr et al 2010;Verhaak et al 2010;Brennan et al 2013;Zheng et al 2013). Here, we expand our knowledge of GBM by evaluating heterogeneity in a large number of primary tumor samples from TCGA as well as through a comparison of pre-and post-treatment GBM tumor pairs.…”

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

“…5A), a frequency similar to that seen with glioblastoma (23%). 41,42 In an analysis of RNA sequencing data, we identified fusion transcripts in 265 lower-grade gliomas (Table S6 [Supplementary Appendix 5]), and correlation with structural genomic variants suggested chimeric transcription for 44% of the high-confidence chromosomal rearrangements, including two EGFR fusions (Fig. 5B), and for 58% of DM-BERs.…”