Expression signatures of DNA repair genes correlate with survival prognosis of astrocytoma patients
Juliana Ferreira de Sousa,
Raul Torrieri,
Rodolfo Bortolozo Serafim,
Luis Fernando Macedo Di Cristofaro,
Fábio Dalbon Escanfella,
Rodrigo Ribeiro,
Dalila Lucíola Zanette,
Maria Luisa Paçó-Larson,
Wilson Araujo da Silva,
Daniela Pretti da Cunha Tirapelli,
Luciano Neder,
Carlos Gilberto Carlotti,
Valeria Valente
Affiliations
Juliana Ferreira de Sousa
Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Raul Torrieri
FAEPA, Center for Medical Genomics (CMG) of the Clinical Hospital, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Rodolfo Bortolozo Serafim
Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Luis Fernando Macedo Di Cristofaro
Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Fábio Dalbon Escanfella
Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Rodrigo Ribeiro
Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Dalila Lucíola Zanette
National Institute of Science and Technology in Stem cell and Cell Therapy, Ribeirão Preto, Brazil
Maria Luisa Paçó-Larson
Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Wilson Araujo da Silva
Center for Integrative Systems Biology (CISBi), NAP/USP, Ribeirão Preto, Brazil
Daniela Pretti da Cunha Tirapelli
Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Luciano Neder
Department of Pathology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Carlos Gilberto Carlotti
Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
Valeria Valente
Center for Integrative Systems Biology (CISBi), NAP/USP, Ribeirão Preto, Brazil
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.