Identification of gene expression and DNA methylation of SERPINA5 and TIMP1 as novel prognostic markers in lower-grade gliomas

Wen-Jing Zeng; Yong-Long Yang; Zhi-Peng Wen; Peng Chen; Xiao-Ping Chen; Zhi-Cheng Gong

doi:10.7717/peerj.9262

Identification of gene expression and DNA methylation of SERPINA5 and TIMP1 as novel prognostic markers in lower-grade gliomas

PeerJ. 2020 Jun 3:8:e9262. doi: 10.7717/peerj.9262. eCollection 2020.

Authors

Wen-Jing Zeng^{1

2

3

4}, Yong-Long Yang⁵, Zhi-Peng Wen^{1

2}, Peng Chen^{1

2}, Xiao-Ping Chen^{1

2}, Zhi-Cheng Gong^{3

4}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China.
³ Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁵ Department of Clinical Pharmacology Research Center, Changsha Carnation Geriatrics Hospital, Changsha, Hunan, China.

Abstract

Background: Lower-grade gliomas (LGGs) is characteristic with great difference in prognosis. Due to limited prognostic biomarkers, it is urgent to identify more molecular markers to provide a more objective and accurate tumor classification system for LGGs.

Methods: In the current study, we performed an integrated analysis of gene expression data and genome-wide methylation data to determine novel prognostic genes and methylation sites in LGGs.

Results: To determine genes that differentially expressed between 44 short-term survivors (<2 years) and 48 long-term survivors (≥2 years), we searched LGGs TCGA RNA-seq dataset and identified 106 differentially expressed genes. SERPINA5 and TIMP1 were selected for further study. Kaplan-Meier plots showed that SERPINA5 and TIMP1 expression were significantly correlated with overall survival (OS) and relapse-free survival (RFS) in TCGA LGGs patients. We next validated the correlation between the candidate genes expression and clinical outcome in CGGA LGGs patients. Multivariate analysis showed that TIMP1 mRNA expression had a significant prognostic value independent of other variables (HR = 4.825, 95% CI = 1.370-17.000, P = 0.014). Then, differential methylation sites were identified from differentially candidate gene expression groups, and all four methylation sites were significantly negatively correlated with gene expression (spearman r < - 0.5, P < 0.0001). Moreover, hyper-methylation of four methylation sites indicated better OS (P < 0.05), and three of them also shown statistical significantly association with better RFS, except for SERPINA5 cg15509705 (P = 0.0762).

Conclusion: Taken together, these findings indicated that the gene expression and methylation of SERPINA5 and TIMP1 may serve as prognostic predictors in LGGs and may help to precise the current histology-based tumors classification system and to provide better stratification for future clinical trials.

Keywords: Bioinformatics analysis; DNA methylation; Lower-grade glioma; Prognostic markers; SERPINA5; TIMP1.

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81903663, No.81803582, No.81703622), National key R&D program (No.2017YFC0909302). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.