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


METHODS
We 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.


RESULTS
We 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.


CONCLUSIONS
Utilizing 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.
Department of Internal Medicine, Division of Hematology/Oncology and UC Brain Tumor Center, University of Cincinnati, Cincinnati OH, USA.
John M
JM
Furgason
Department of Internal Medicine, Division of Hematology/Oncology and UC Brain Tumor Center, University of Cincinnati, Cincinnati OH, USA.
Robert F
RF
Koncar
Department of Neurosurgery, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA.
Sharon K
SK
Michelhaugh
Department of Pathology, Wayne State University College of Medicine, Detroit, MI, USA.
Fazlul H
FH
Sarkar
Department of Neurosurgery, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA.
Sandeep
S
Mittal
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; Department of Neurological Surgery, University Hospitals Case Medical Center, Cleveland, Ohio, USA.
Andrew E
AE
Sloan
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Jill S
JS
Barnholtz-Sloan
Department of Internal Medicine, Division of Hematology/Oncology and UC Brain Tumor Center, University of Cincinnati, Cincinnati OH, USA.
El Mustapha
el M
Bahassi
CDK4; EGFR; MDM2; chromothripsis; glioblastoma