title: DNA copy number analysis of Grade II-III and Grade IV gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status.
abstract: BACKGROUND
  Isocitrate dehydrogenase (IDH) mutation status and grade define subgroups of diffuse gliomas differing based on age, tumor location, presentation, and prognosis. While some biologic differences between IDH mutated (IDH (mut)) and wild-type (IDH (wt)) gliomas are clear, the distinct alterations associated with progression of the two subtypes to glioblastoma (GBM, Grade IV) have not been well described. We analyzed copy number alterations (CNAs) across grades (Grade II-III and GBM) in both IDH (mut) and IDH (wt) infiltrating gliomas using molecular inversion probe arrays.
  
  
  RESULTS
  Ninety four patient samples were divided into four groups: Grade II-III IDH (wt) (n = 17), Grade II-III IDH (mut) (n = 28), GBM IDH (wt) (n = 25), and GBM IDH (mut) (n = 24). We validated prior observations that IDH (wt) GBM have a high frequency of chromosome 7 gain (including EGFR) and chromosome 10 loss (including PTEN) compared with IDH (mut) GBM. Hierarchical clustering of IDH (mut) gliomas demonstrated distinct CNA patterns distinguishing lower grade gliomas versus GBM. However, similar hierarchical clustering of IDH (wt) gliomas demonstrated no CNA distinction between lower grade glioma and GBM. Functional analyses showed that IDH (wt) gliomas had more chromosome gains in regions containing receptor tyrosine kinase pathways. In contrast, IDH (mut) gliomas more commonly demonstrated amplification of cyclins and cyclin dependent kinase genes. One of the most common alterations associated with transformation of lower grade to GBM IDH (mut) gliomas was the loss of chromosomal regions surrounding PTEN. IDH (mut) GBM tumors demonstrated significantly higher levels of overall CNAs compared to lower grade IDH (mut) tumors and all grades of IDH (wt) tumors, and IDH (mut) GBMs also demonstrated significant increase in incidence of chromothripsis.
  
  
  CONCLUSIONS
  Taken together, these analyses demonstrate distinct molecular ontogeny between IDH (wt) and IDH (mut) gliomas. Our data also support the novel findings that malignant progression of IDH (mut) gliomas to GBM involves increased genomic instability and genomic catastrophe, while IDH (wt) lower grade tumors are virtually identical to GBMs at the level of DNA copy number alterations.
authors.affiliation: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA. adam.cohen@hci.utah.edu.
authors.forename: Adam
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Children's Hospital, University of Iowa, 200 Hawkins Dr, 2524 JCP, Iowa City, IA, 52242, USA. mariko-sato@uiowa.edu.
authors.forename: Mariko
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, Houston, TX, 77030, USA. Ken.Aldape@uhn.ca.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA. Clint.Mason@hci.utah.edu.
authors.forename: Clinton C
authors.initials: CC
authors.lastname: Mason
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, Houston, TX, 77030, USA. KDAlfaro@mdanderson.org.
authors.forename: Kristin
authors.initials: K
authors.lastname: Alfaro-Munoz
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, Houston, TX, 77030, USA. heathcoc@bcm.edu.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Heathcock
authors.affiliation: ARUP Laboratories, Salt Lake City, UT, 84112, USA. Sarah.South@hsc.utah.edu.|Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA. Sarah.South@hsc.utah.edu.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: South
authors.affiliation: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA. Lisa.Abegglen@hci.utah.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Abegglen
authors.affiliation: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA. joshua.schiffman@hci.utah.edu.|Department of Pediatrics, University of Utah, Salt Lake City, UT, 84112, USA. joshua.schiffman@hci.utah.edu.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schiffman
authors.affiliation: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA. Howard.Colman@hci.utah.edu.
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
mesh_terms: D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D063990:Gene Ontology; D005910:Glioma / Q000145:classification / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D016019:Survival Analysis
chemical_list: D007521:Isocitrate Dehydrogenase