Abstract
Purpose
The WHO classification for IDH-mutant grade II and grade III astrocytoma may not be as prognostically meaningful as expected. We aimed to develop a novel classification system based on the DNA damage response signature.
Methods
We developed the gene signature of DNA damage response with 115 samples from The Cancer Genome Atlas (TCGA) database. The dataset from Chinese Glioma Genome Atlas (CGGA) database with 41 samples was used as the validation set. Lasso Cox regression model was applied for selection of the best signature. Gene set enrichment analysis (GSEA) and gene ontology (GO) analysis were implemented to reveal its biological phenotype.
Results
A two-gene DNA damage response signature (RAD18, MSH2) was developed using the lasso Cox regression model based on the TCGA dataset. Its prognostic efficiency was validated in the CGGA cohort. The result of Cox regression analysis showed that the signature has a better predictive accuracy than the WHO grade. The risk score was an independent prognostic factor for the overall survival of the IDH-mutant grade II and grade III astrocytoma. GSEA and GO analysis confirmed enhanced processes related to DNA damage response in high-risk group.
Conclusion
We developed a two-gene signature which can effectively predict the prognosis of patients with IDH-mutant grade II and grade III astrocytoma. It suggests a novel classification of astrocytoma with better prognostic accuracy based on the expression of DNA damage response genes.
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Acknowledgements
We appreciate the generosity of TCGA network for sharing the huge amount of data.
Funding
This work was supported by funding from the National Key Research and Development Plan (No. 2016YFC0902500), National Natural Science Foundation of China (No. 81903060) and Beijing Tiantan Hospital Miaopu Project (No. 2017MP05).
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432_2020_3132_MOESM1_ESM.tif
Supplementary Figure 1 Kaplan-Meier curve stratified by RAD18 and MSH2 expression in TCGA and CGGA cohort. (A) Kaplan-Meier curve stratified by RAD18 for patients in the TCGA cohort, low expression group versus high expression group (P=0.0199). (B) Kaplan-Meier curve stratified by MSH2 for patients in the TCGA cohort, low expression group versus high expression group (P=0.1463). (C) Kaplan-Meier curve stratified by RAD18 for patients in the CGGA cohort, low expression group versus high expression group (P=0.0526). (D) Kaplan-Meier curve stratified by MSH2 for patients in the CGGA cohort, low expression group versus high expression group (P=0.2016). (TIF 2145 kb)
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Liu, Q., Wang, K., Huang, R. et al. A novel DNA damage response signature of IDH-mutant grade II and grade III astrocytoma at transcriptional level. J Cancer Res Clin Oncol 146, 579–591 (2020). https://doi.org/10.1007/s00432-020-03132-x
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DOI: https://doi.org/10.1007/s00432-020-03132-x