title: Senescence-associated-gene signature identifies genes linked to age, prognosis, and progression of human gliomas.
abstract: BACKGROUND
  Senescence-associated genes (SAGs) are responsible for the senescence-associated secretory phenotype, linked in turn to cellular aging, the aging brain, and the pathogenesis of cancer.
  
  
  OBJECTIVE
  We hypothesized that senescence-associated genes are overexpressed in older patients, in higher grades of glioma, and portend a poor prognosis.
  
  
  METHODS
  Forty-seven gliomas were arrayed on a custom version of the Affymetrix HG-U133+2.0 GeneChip, for expression of fourteen senescence-associated genes: CCL2, CCL7, CDKN1A, COPG, CSF2RB, CXCL1, ICAM-1, IGFBP-3, IL-6, IL-8, SAA4, TNFRSF-11B, TNFSF-11 and TP53. A combined "senescence score" was generated using principal component analysis to measure the combined effect of the senescence-associated gene signature.
  
  
  RESULTS
  An elevated senescence score correlated with older age (r=0.37; P=.01) as well as a higher degree of malignancy, as determined by WHO, histological grade (r=0.49; P<.001). There was a mild association with poor prognosis (P=.06). Gliosarcomas showed the highest scores. Six genes independently correlated with either age (IL-6, TNFRSF-11B, IGFBP-3, SAA4, and COPG), prognosis (IL-6, SAA4), or the grade of the glioma (IL-6, IL-8, ICAM-1, IGFBP-3, and COPG).
  
  
  CONCLUSIONS
  We report: 1) a novel molecular signature in human gliomas, based on cellular senescence, translating the concept of SAG to human cancer; 2) the senescence signature is composed of genes central to the pathogenesis of gliomas, defining a novel, aggressive subtype of glioma; and 3) these genes provide prognostic biomarkers, as well as targets, for drug discovery and immunotherapy.
authors.affiliation: Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Experimental Therapeutics, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Gastrointestinal, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; M2Gen, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Senior Oncology Programs, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
authors.forename: Lodovico
authors.initials: L
authors.lastname: Balducci
authors.affiliation: Biostatistics and Bioinformatics Department, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.affiliation: Merck Laboratory.
authors.forename: Andrey
authors.initials: A
authors.lastname: Loboda
authors.affiliation: Neuro-Oncology/Neurosurgery, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Merck Laboratory.
authors.forename: Michael
authors.initials: M
authors.lastname: Nebozhyn
authors.affiliation: Population Sciences Division, Department of Oncological Sciences, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
authors.forename: Aileen
authors.initials: A
authors.lastname: Staller
authors.affiliation: Biostatistics and Bioinformatics Department, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Fulp
authors.affiliation: Experimental Therapeutics, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; M2Gen, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
authors.forename: William
authors.initials: W
authors.lastname: Dalton
authors.affiliation: Experimental Therapeutics, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Gastrointestinal, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Neuro-Oncology/Neurosurgery, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Gibbs Cancer Center & Research Institute, Spartanburg, SC 29303 USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Yeatman
authors.affiliation: Experimental Therapeutics, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Population Sciences Division, Department of Oncological Sciences, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Neuro-Oncology/Neurosurgery, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: steven.brem@uphs.upenn.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Brem
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D001921:Brain; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D025341:Principal Component Analysis; D011379:Prognosis; D012720:Severity of Illness Index; D016019:Survival Analysis
keywords: Aging; Astrocytoma; Biomarker; Genomics; Glioblastoma; Interleukin-6; Senescence