Domenico Coppola1, Lodovico Balducci2, Dung-Tsa Chen3, Andrey Loboda4, Michael Nebozhyn5, Aileen Staller6, William J Fulp3, William Dalton7, Timothy Yeatman8, Steven Brem9. 1. 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. 2. Senior Oncology Programs, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA. 3. Biostatistics and Bioinformatics Department, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA. 4. Merck Laboratory. 5. Neuro-Oncology/Neurosurgery, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Merck Laboratory. 6. Population Sciences Division, Department of Oncological Sciences, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA. 7. Experimental Therapeutics, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; M2Gen, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA. 8. 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. 9. 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.
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). CONCLUSION: 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.
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). CONCLUSION: We report: 1) a novel molecular signature in humangliomas, based on cellular senescence, translating the concept of SAG to humancancer; 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: Kalil G Abdullah; Ashwin Ramayya; Jayesh P Thawani; Lukasz Macyszyn; Maria Martinez-Lage; Donald M O'Rourke; Steven Brem Journal: PLoS One Date: 2015-05-15 Impact factor: 3.240
Authors: John C Nolan; Manuela Salvucci; Steven Carberry; Ana Barat; Miguel F Segura; Justine Fenn; Jochen H M Prehn; Raymond L Stallings; Olga Piskareva Journal: Front Cell Dev Biol Date: 2020-11-20
Authors: Mohammed Jaber; Christian Ewelt; Johannes Wölfer; Benjamin Brokinkel; Christian Thomas; Martin Hasselblatt; Oliver Grauer; Walter Stummer Journal: Neurosurgery Date: 2019-06-01 Impact factor: 4.654