Original ArticleIdentification of a DNA Repair-Related Multigene Signature as a Novel Prognostic Predictor of Glioblastoma
Introduction
Glioma is a well-known and aggressive malignant tumor associated with short survival and a uniformly fatal outcome despite the availability of advanced therapies.1, 2 According to the World Health Organization, gliomas are divided into 4 grades (I–IV).3 Grades II and III are considered lower-grade gliomas,4 whereas grade IV is glioblastoma multiforme (GBM) and is the most malignant type of glioma.5 The wide range of biological and clinical heterogeneity makes the diagnosis and treatment of gliomas an enormous challenge.6 One confounding factor is interobserver variability arising from a morphology-based classification of gliomas that results in suboptimal diagnostic reproducibility.6 Thus, there is an urgent need to develop objective and accurate methods for the diagnosis and treatment of gliomas.
With the advent of new gene profiles, many researchers have presented various overall survival (OS) prediction models4, 7, 8, 9; however, few of these studies focused on treatment selection in cases of primary glioblastoma multiforme (pGBM). In addition, why many patients with pGBM are resistant to temozolomide (TMZ) therapy remains unclear.
As a new oral alkylating agent, TMZ is currently the gold standard for adjuvant chemotherapy in patients with gliomas, especially for high-grade glioma.10 Although O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is an important biomarker to divide gliomas into TMZ-chemoresistant (TCR subtype) and TMZ-chemosensitive (TCS subtype) groups,7, 11 many patients with glioma and MGMT promoter methylation do not benefit from TMZ therapy.12 Therefore, there is the need to identify other biomarkers that better discriminate patients to provide better personalized treatment care and response to TMZ.
In the present study, we selected 89 patients with pGBM from the Chinese Glioma Genome Atlas (CGGA) RNA-seq dataset as a training set, used patients from The Cancer Genome Atlas (TCGA) RNA-seq and GSE16011 mRNA array sets as validation sets, and identified a 5-gene signature composed of APEX1, APRT, PARP2, PMS2L2, and POLR2L that reliably predicts OS of patients with glioma and identifies subtypes of pGBM with differing responses to TMZ therapy. The identification and characterization of our gene panel may provide a new method for the accurate diagnosis and effective treatment of pGBM.
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Ethical Approval
The gliomas tissue collection was approved by the institutional review board of Beijing Tiantan Hospital affiliated with Capital Medical University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Informed Consent
Informed consent was obtained prospectively from all individual participants in this
Determination of a 5-Gene Signature for Prognostic Prediction of pGBM
One-hundred twenty-seven genes involved in DNA repair or mismatch repair were identified from the Gene Set Enrichment Analysis website. Based on our comparison between TMZ-treated and -untreated groups, we identified differentially expressed genes of which 1130 genes were up-regulated and 375 genes were down-regulated in the TMZ-treated group (P < 0.05). Using univariate Cox regression analysis, we identified 2428 genes that were significantly associated with patient OS. After overlapping these
Discussion
Gliomas are the most common group of primary malignant tumors of the central nervous system, causing cancer-related deaths worldwide.18, 19 Despite efforts to develop many therapeutic options including surgery, radiotherapy, and chemotherapy to improve glioma outcome, no major improvement has been reported.4
A major advance in GBM therapy was the discovery that the DNA alkylating agent TMZ confers improved patient survival20; however, not all patients with GBM benefit from aggressive therapy.
Conclusions
In our study, we identified and validated a 5-gene signature in patients with pGBM, which discriminated these patients into high- or low-risk groups with different OS. It is recommended that those patients with a low-risk score should receive TMZ therapy to lengthen their OS. Moreover, future efforts should strive to develop new treatment therapies for improved care for those patients with a high-risk score.
Acknowledgments
We acknowledge CGGA and TCGA for sample collection and clinical data retrieval.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Shuai Jin and Zenghui Qian contributed equally to this paper.