PMID- 26328271
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150902
LR  - 20200930
IS  - 2331-4737 (Print)
IS  - 2331-4737 (Electronic)
IS  - 2331-4737 (Linking)
VI  - 2
IP  - 7
DP  - 2015
TI  - Whole genome sequence analysis links chromothripsis to EGFR, MDM2, MDM4, and CDK4 
      amplification in glioblastoma.
PG  - 618-28
AB  - 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.
FAU - Furgason, John M
AU  - Furgason JM
AD  - Department of Internal Medicine, Division of Hematology/Oncology and UC Brain 
      Tumor Center, University of Cincinnati, Cincinnati OH, USA.
FAU - Koncar, Robert F
AU  - Koncar RF
AD  - Department of Internal Medicine, Division of Hematology/Oncology and UC Brain 
      Tumor Center, University of Cincinnati, Cincinnati OH, USA.
FAU - Michelhaugh, Sharon K
AU  - Michelhaugh SK
AD  - Department of Neurosurgery, Wayne State University and Karmanos Cancer Institute, 
      Detroit, MI, USA.
FAU - Sarkar, Fazlul H
AU  - Sarkar FH
AD  - Department of Pathology, Wayne State University College of Medicine, Detroit, MI, 
      USA.
FAU - Mittal, Sandeep
AU  - Mittal S
AD  - Department of Neurosurgery, Wayne State University and Karmanos Cancer Institute, 
      Detroit, MI, USA.
FAU - Sloan, Andrew E
AU  - Sloan AE
AD  - 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.
FAU - Barnholtz-Sloan, Jill S
AU  - Barnholtz-Sloan JS
AD  - Case Comprehensive Cancer Center, Case Western Reserve University School of 
      Medicine, Cleveland, OH, USA.
FAU - Bahassi, El Mustapha
AU  - Bahassi el M
AD  - Department of Internal Medicine, Division of Hematology/Oncology and UC Brain 
      Tumor Center, University of Cincinnati, Cincinnati OH, USA.
LA  - eng
PT  - Journal Article
DEP - 20150731
PL  - United States
TA  - Oncoscience
JT  - Oncoscience
JID - 101636666
PMC - PMC4549359
OTO - NOTNLM
OT  - CDK4
OT  - EGFR
OT  - MDM2
OT  - chromothripsis
OT  - glioblastoma
COIS- CONFLICT OF INTEREST With regard to the data presented in this manuscript, the 
      authors declare no conflict of interest.
EDAT- 2015/09/04 06:00
MHDA- 2015/09/04 06:01
PMCR- 2015/07/31
CRDT- 2015/09/02 06:00
PHST- 2015/06/01 00:00 [received]
PHST- 2015/07/25 00:00 [accepted]
PHST- 2015/09/02 06:00 [entrez]
PHST- 2015/09/04 06:00 [pubmed]
PHST- 2015/09/04 06:01 [medline]
PHST- 2015/07/31 00:00 [pmc-release]
AID - 178 [pii]
AID - 10.18632/oncoscience.178 [doi]
PST - epublish
SO  - Oncoscience. 2015 Jul 31;2(7):618-28. doi: 10.18632/oncoscience.178. eCollection 
      2015.