title: Integrated genomic analysis of survival outliers in glioblastoma.
abstract: To elucidate molecular features associated with disproportionate survival of glioblastoma (GB) patients, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide); "GB outliers" were identified: long-term survivor of 33 months (LTS; n = 8) versus short-term survivor of 7 months (STS; n = 10).
  
  
  
  We implemented exome, RNA, whole genome sequencing, and DNA methylation for collection of deep genomic data from STS and LTS GB patients.
  
  
  
  LTS GB showed frequent chromosomal gains in 4q12 (platelet derived growth factor receptor alpha and KIT) and 12q14.1 (cyclin-dependent kinase 4), and deletion in 19q13.33 (BAX, branched chain amino-acid transaminase 2, and cluster of differentiation 33). STS GB showed frequent deletion in 9p11.2 (forkhead box D4-like 2 and aquaporin 7 pseudogene 3) and 22q11.21 (Hypermethylated In Cancer 2). LTS GB showed 2-fold more frequent copy number deletions compared with STS GB. Gene expression differences showed the STS cohort with altered transcriptional regulators: activation of signal transducer and activator of transcription (STAT)5a/b, nuclear factor-kappaB (NF-κB), and interferon-gamma (IFNG), and inhibition of mitogen-activated protein kinase (MAPK1), extracellular signal-regulated kinase (ERK)1/2, and estrogen receptor (ESR)1. Expression-based biological concepts prominent in the STS cohort include metabolic processes, anaphase-promoting complex degradation, and immune processes associated with major histocompatibility complex class I antigen presentation; the LTS cohort features genes related to development, morphogenesis, and the mammalian target of rapamycin signaling pathway. Whole genome methylation analyses showed that a methylation signature of 89 probes distinctly separates LTS from STS GB tumors.
  
  
  
  We posit that genomic instability is associated with longer survival of GB (possibly with vulnerability to standard therapy); conversely, genomic and epigenetic signatures may identify patients where up-front entry into alternative, targeted regimens would be a preferred, more efficacious management.
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.|Department of Biomedical Informatics, Arizona State University, Scottsdale, Arizona, USA.
authors.forename: Sen
authors.initials: S
authors.lastname: Peng
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
authors.forename: Harshil
authors.initials: H
authors.lastname: Dhruv
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
authors.forename: Brock
authors.initials: B
authors.lastname: Armstrong
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, Arizona, USA.
authors.forename: Bodour
authors.initials: B
authors.lastname: Salhia
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, Arizona, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, Arizona, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kiefer
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
authors.forename: Julianna
authors.initials: J
authors.lastname: Parks
authors.affiliation: Case Comprehensive Cancer Center, Case Western University, Cleveland, Ohio, USA.
authors.forename: Selene
authors.initials: S
authors.lastname: Virk
authors.affiliation: Case Comprehensive Cancer Center, Case Western University, Cleveland, Ohio, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Sloan
authors.affiliation: Case Comprehensive Cancer Center, Case Western University, Cleveland, Ohio, USA.
authors.forename: Quinn T
authors.initials: QT
authors.lastname: Ostrom
authors.affiliation: Case Comprehensive Cancer Center, Case Western University, Cleveland, Ohio, USA.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Barnholtz-Sloan
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.|Departments of Cancer Biology and Neurosurgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.|Translational Genomic Research Institute, Phoenix, Arizona, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D023281:Genomics / Q000379:methods*; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D017741:Survivors / Q000706:statistics & numerical data*; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor
keywords: genome sequencing; glioblastoma; outlier; responders; survival difference