Peer Review #1 of "Identification and validation of a three-gene signature as a candidate prognostic biomarker for lower grade glioma (v0.1)"

Abstract

Background Lower grade glioma (LGG) are a heterogeneous tumor that may develop into high-grade malignant glioma seriously shortens patient survival time. The clinical prognostic biomarker of lowergrade glioma is still lacking. The aim of our study is to explore novel biomarkers for LGG that contribute to distinguish potential malignancy in low-grade glioma, to guide clinical adoption of more rational and effective treatments. Methods The RNA-seq data for LGG was downloaded from the UCSC Xena and Chinese Glioma Genome Atlas (CGGA). By robust likelihood-based survival model, LASSO regression and multivariate Cox regression analysis, we developed a three-gene signature and established a risk score to predict the prognosis of patient with LGG. The three-gene signature was an independent survival predictor compared to other clinical parameters. Based on the signature related risk score system, stratified survival analysis was performed in patients with different age group, gender, and pathologic grade. The prognostic signature was validated in CGGA dataset. Finally, Weighted Gene Co-expression Network Analysis (WGCNA) was carried out to find the co-expression genes related to the member of the signature and enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were conducted for those co-expression network. To prove the efficiency of the model, timedependent ROC curves of our model and other models are constructed. Results In this study, a three-gene signature (WEE1, CRTAC1, SEMA4G) was constructed. Based on the model, the risk score of each patient was calculated with LGG (low-risk vs. high-risk, hazard ratio[HR]=0.198, 95%CI= 0.120-0.325) and patients in the high-risk group had significantly poorer survival results than those in the low-risk group. Furthermore，the model was validated in CGGA dataset. Lastly, by WGCNA, we constructed the co-expression network of the three genes and conducted the enrichment of GO and KEGG. Our study identified a three-gene model that showed satisfactory performance in predicting the 1-, 3-and 5-year survival of LGG patients compared to other models and may be promising independent biomarker of LGG.