title: Expression signatures of DNA repair genes correlate with survival prognosis of astrocytoma patients.
abstract: Astrocytomas are the most common primary brain tumors. They are very resistant to therapies and usually progress rapidly to high-grade lesions. Here, we investigated the potential role of DNA repair genes in astrocytoma progression and resistance. To this aim, we performed a polymerase chain reaction array-based analysis focused on DNA repair genes and searched for correlations between expression patters and survival prognoses. We found 19 genes significantly altered. Combining these genes in all possible arrangements, we found 421 expression signatures strongly associated with poor survival. Importantly, five genes (DDB2, EXO1, NEIL3, BRCA2, and BRIP1) were independently correlated with worse prognoses, revealing single-gene signatures. Moreover, silencing of EXO1, which is remarkably overexpressed, promoted faster restoration of double-strand breaks, while NEIL3 knockdown, also highly overexpressed, caused an increment in DNA damage and cell death after irradiation of glioblastoma cells. These results disclose the importance of DNA repair pathways for the maintenance of genomic stability of high-grade astrocytomas and suggest that EXO1 and NEIL3 overexpression confers more efficiency for double-strand break repair and resistance to reactive oxygen species, respectively. Thereby, we highlight these two genes as potentially related with tumor aggressiveness and promising candidates as novel therapeutic targets.
authors.affiliation: 1 Department of Clinical Analysis, Faculty of Pharmaceutical Sciences of Araraquara, University of São Paulo State, Araraquara, Brazil.|2 Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Juliana Ferreira
authors.initials: JF
authors.lastname: de Sousa
authors.affiliation: 3 FAEPA, Center for Medical Genomics (CMG) of the Clinical Hospital, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Raul
authors.initials: R
authors.lastname: Torrieri
authors.affiliation: 1 Department of Clinical Analysis, Faculty of Pharmaceutical Sciences of Araraquara, University of São Paulo State, Araraquara, Brazil.|2 Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Rodolfo Bortolozo
authors.initials: RB
authors.lastname: Serafim
authors.affiliation: 1 Department of Clinical Analysis, Faculty of Pharmaceutical Sciences of Araraquara, University of São Paulo State, Araraquara, Brazil.|2 Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Luis Fernando Macedo
authors.initials: LF
authors.lastname: Di Cristofaro
authors.affiliation: 2 Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Fábio Dalbon
authors.initials: FD
authors.lastname: Escanfella
authors.affiliation: 2 Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Ribeiro
authors.affiliation: 4 Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.|5 Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy-CEPID/FAPESP, Ribeirão Preto, Brazil.|6 National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil.
authors.forename: Dalila Lucíola
authors.initials: DL
authors.lastname: Zanette
authors.affiliation: 2 Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Paçó-Larson
authors.affiliation: 4 Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.|5 Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy-CEPID/FAPESP, Ribeirão Preto, Brazil.|6 National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil.|7 Center for Integrative Systems Biology (CISBi), NAP/USP, Ribeirão Preto, Brazil.
authors.forename: Wilson Araujo
authors.initials: WA
authors.lastname: da Silva
authors.affiliation: 8 Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Daniela Pretti da Cunha
authors.initials: DP
authors.lastname: Tirapelli
authors.affiliation: 9 Department of Pathology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Luciano
authors.initials: L
authors.lastname: Neder
authors.affiliation: 7 Center for Integrative Systems Biology (CISBi), NAP/USP, Ribeirão Preto, Brazil.|8 Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
authors.forename: Carlos Gilberto
authors.initials: CG
authors.lastname: Carlotti
authors.affiliation: 1 Department of Clinical Analysis, Faculty of Pharmaceutical Sciences of Araraquara, University of São Paulo State, Araraquara, Brazil.|2 Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.|7 Center for Integrative Systems Biology (CISBi), NAP/USP, Ribeirão Preto, Brazil.
authors.forename: Valeria
authors.initials: V
authors.lastname: Valente
mesh_terms: D017209:Apoptosis; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D009699:N-Glycosyl Hydrolases / Q000235:genetics / Q000378:metabolism; D011379:Prognosis
chemical_list: C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; D009699:N-Glycosyl Hydrolases; C468764:NEIL3 protein, human; D045643:DNA Repair Enzymes
keywords: DNA repair; astrocytoma; genomic instability; glioblastoma; tumor progression