Expression signatures of DNA repair genes correlate with survival prognosis of astrocytoma patients

Made available in DSpace on 2022-04-29T08:45:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-04-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 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. Department of Clinical Analysis Faculty of Pharmaceutical Sciences of Araraquara University of São Paulo State Department of Cellular and Molecular Biology Ribeirão Preto Medical School University of São Paulo (USP) FAEPA Center for Medical Genomics (CMG) of the Clinical Hospital Ribeirão Preto Medical School University of São Paulo (USP) Department of Genetics Ribeirão Preto Medical School University of São Paulo (USP) Regional Blood Center of Ribeirão Preto and Center for Cell-Based Therapy—CEPID/FAPESP National Institute of Science and Technology in Stem cell and Cell Therapy Center for Integrative Systems Biology (CISBi) NAP/USP Department of Surgery and Anatomy Ribeirão Preto Medical School University of São Paulo (USP) Department of Pathology Ribeirão Preto Medical School University of São Paulo (USP) FAPESP: 2013/13465-1