Identification of a DNA Repair-Related Multigene Signature as a Novel Prognostic Predictor of Glioblastoma
WORLD NEUROSURGERY
Authors: Jin, Shuai; Qian, Zenghui; Liang, Tingyu; Liang, Jingshan; Yang, Fuqiang; Sun, Lihua; Li, Wenbin; Qiu, Xiaoguang; Zhang, Man
Abstract
BACKGROUND: Glioblastoma (GBM) is an extremely challenging malignancy to treat. Although temozolomide (TMZ) is a standard treatment regimen, many patients with GBM develop chemoresistance. The aim of this study was to identify a DNA repair-related gene signature to better stratify patients treated with TMZ. METHODS: We selected 89 cases of primary GBM (pGBM) from the Chinese Glioma Genome Atlas RNA-seq dataset as the training cohort, whereas The Cancer Genome Atlas RNA-seq and Gene Set Enrichment (GSE) 16011 mRNA array sets were used as validation cohorts. Regression analysis and linear risk score assessment were performed to build a DNA repair-related signature. We used Kaplan-Meier analysis to evaluate the predictive value of the signature for overall survival (OS) in the different groups. Multivariate Cox regression analysis was used to determine whether the 5-gene signature could independently predict OS. RESULTS: Using our 5-gene signature panel of APEX1, APRT, PARP2, PMS2L2, and POLR2L, we divided patients with pGBM into high-and low-risk groups. Patients with a low-risk score were predicted to have favorable survival and greater benefit from TMZ therapy compared with patients from the high-risk group (P<0.05). Moreover, receiver operating characteristic curves showed that the multigene signature was the most sensitive and specific model for survival prediction (P<0.05). CONCLUSIONS: Among patients with pGBM, classification based on a risk score determined using a 5-gene panel indicated different OS and reaction to TMZ. The findings in this study demonstrate that this unique 5-gene signature could be a novel model to predict OS and provide accurate therapy for patients with pGBM.
Increased human AP endonuclease 1 level confers protection against the paternal age effect in mice
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Authors: Sanchez, Jamila R.; Reddick, Traci L.; Perez, Marissa; Centonze, Victoria E.; Mitra, Sankar; Izumi, Tadahide; McMahan, C. Alex; Walter, Christi A.
Abstract
Increased paternal age is associated with a greater risk of producing children with genetic disorders originating from de novo germline mutations. Mice mimic the human condition by displaying an age-associated increase in spontaneous mutant frequency in spermatogenic cells. The observed increase in mutant frequency appears to be associated with a decrease in the DNA repair protein, AP endonuclease 1 (APEX1) and Apex1 heterozygous mice display an accelerated paternal age effect as young adults. In this study, we directly tested if APEX1 over-expression in cell lines and transgenic mice could prevent increases in mutagenesis. Cell lines with ectopic expression of APEX1 had increased APEX1 activity and lower spontaneous and induced mutations in the lad reporter gene relative to the control. Spermatogenic cells obtained from mice transgenic for human APEX1 displayed increased APEX1 activity, were protected from the age-dependent increase in spontaneous germline mutagenesis, and exhibited increased apoptosis in the spermatogonial cell population. These results directly indicate that increases in APEXI level confer protection against the murine paternal age effect, thus highlighting the role of APEX1 in preserving reproductive health with increasing age and in protection against genotoxin-induced mutagenesis in somatic cells. (C) 2015 Elsevier B.V. All rights reserved.
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