Whole genome sequence analysis links chromothripsis to EGFR, MDM2, MDM4, and CDK4 amplification in glioblastoma

Abstract

BackgroundFindings based on recent advances in next-generation sequence analysis suggest that, in some tumors, a single catastrophic event, termed chromothripsis, results in several simultaneous tumorigenic alterations. Previous studies have suggested that glioblastoma (GBM) may exhibit chromothripsis at a higher rate (39%) than other tumors (9%). Primary glioblastoma is an aggressive form of brain cancer that typically appears suddenly in older adults. With aggressive treatment, the median survival time is only 15 months. Their acute onset and widespread genomic instability indicates that chromothripsis may play a key role in their initiation and progression. GBMs are often characterized by EGFR amplification, CDKN2A and PTEN deletion, although approximately 20% of GBMs harbor additional amplifications in MDM2 or MDM4 with CDK4.MethodsWe used the chromothripsis prediction tool, Shatterproof, in conjunction with a custom whole genome sequence analysis pipeline in order to generate putative regions of chromothripsis. The data derived from this study was further expanded on using fluorescence in situ hybridization (FISH) analysis and susceptibility studies with colony formation assays.ResultsWe show that primary GBMs are associated with higher chromothripsis scores and establish a link between chromothripsis and gene amplification of receptor tyrosine kinases (RTKs), as well as modulators of the TP53 and RB1 pathways.ConclusionsUtilizing a newly introduced bioinformatic tool, we provide evidence that chromothripsis is associated with the formation of amplicons containing several oncogenes involved in key pathways that are likely essential for post-chromothriptic cell survival.

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

“…This phenomenon can be caused by IR, BFB cycles, telomere dysfunction, and premature chromosome condensation within micronuclei (Crasta et al, 2012; Leibowitz et al, 2015; Rode et al, 2015; Zhang et al, 2015). In the CNS, high rates of chromotripsis have been found in neuroblastoma (Molenaar et al, 2012), glioblastoma (Furgason et al, 2015) and medulloblastoma (Rausch et al, 2012) (Table 1). While NHEJ and microhomology-mediated break-induced replication (MMBIR) have been proposed as the mechanisms leading to chromothripsis (Forment et al, 2012), it has recently been suggested that micronuclei could be an important step leading to chromothripsis through the defective DNA repair mechanism and replication fork collapse present in micronuclei (Crasta et al, 2012; Rausch et al, 2012).…”

Chromothripsis in Oncology: Literature Review and Case Report

“…В другом исследовании [53] показано, что частота хромотрипсиса в глиобластомах была намного выше (39 %), чем в других опухолях (9 %). При этом имели место важные молекулярные сдвиги, касающиеся генов EGFR, MDM2, MDM4 и CDK4.…”

Chromothripsis in Treatment Resistance in Multiple Myeloma

“…The causes and consequences of chromothripsis might be exploited by the use of molecularly targeted therapies, such as epidermal growth factor receptor‒targeted therapy for the treatment of glioblastoma [16]. Chromothripsis affects the functions and expression of a considerable number of genes, and this could be associated with the response to particular drugs [17].…”

“…Despite chromothripsis being widely reported in many cancers, the exact criteria and the role of copy number alterations have yet to be standardized [16]. Previous studies have shown a poor prognosis in patients with chromothripsis and that chromothripsis is associated with the prognosis in several cancers, including malignant melanoma, neuroblastoma, and colorectal cancer.…”