Construction and validation of somatic mutation-derived long non-coding RNAs signatures of genomic instability to predict prognosis of hepatocellular carcinoma

Figure 1 Identification of genomic instability-related long non-coding RNAs in patients with hepatocellular carcinoma. A: The top 20 long non-coding RNAs (LncRNAs) significantly expressed between the genomically unstable (GU) and genomically stable (GS) groups; B: Unsupervised hierarchical clustering analysis was conducted on 374 tumor samples in the TCGA set using 88 differentially expressed LncRNAs. The left orange cluster is the GU-like group, and the right blue cluster is the GS-like group; C: Boxplots of somatic mutations between the GU-like group and GS-like group; D: Boxplots of H2AX expression level in the GU-like group and GS-like group. The expression level of H2AX in the GU-like group is significantly higher than that in the GS-like group. GU: Genomically unstable; GS: Genomically stable.

Figure 2 Functional analysis of the genomic instability-related long non-coding RNAs. A: Co-expression network of genomic instability-related long non-coding RNAs (LncRNAs) and mRNAs. The red circles represent mRNAs, and the blue circles represent LncRNAs; B and C: Functional enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes for mRNAs co-expressed with LncRNAs.

Figure 3 Identification of the genomic instability-derived long non-coding RNAs signature in the training set. A: Forest plot: The P value, risk coefficient (HR) of 13 genomic instability (GI)-long non-coding RNAs (LncRNAs) in the training set analyzed by univariate Cox regression were significantly associated with hepatocellular carcinoma prognosis; B: Kaplan–Meier analysis of overall survival in patients with low or high risk according to the GI-derived LncRNAs signature (GILncSig) score in the training set; C: Time-dependent receiver operating characteristic curves analysis of the GILncSig; D: The LncRNA expression patterns, distribution of somatic mutations, UBQLN4 and H2AX expression with increasing GILncSig score; E: Somatic mutations count in the high-risk and low-risk groups for the training set patients. Red represents the high-risk group, and blue represents the low-risk group; F: The boxplots of UBQLN4 expression and H2AX expression between the high-risk and low-risk groups in the training group.

Figure 4 The genomic instability-derived long non-coding RNAs signature was verified in the testing set and TCGA set. A: Kaplan–Meier survival analysis of the high-risk and low-risk groups in the testing set; B: Time-dependent receiver operating characteristic (ROC) curves analysis of the genomic instability-derived long non-coding RNAs signature (GILncSig) in the testing set; C: Long non-coding RNAs (LncRNAs) expression patterns, distribution of somatic mutations, UBQLN4 and H2AX expression with increasing GILncSig score in the testing set; D: The boxplots of the distribution of somatic mutations between the high-risk and low-risk groups in the testing group; E: The boxplots of the UBQLN4 expression and the H2AX expression between the high-risk and low-risk groups in the testing group; F: Kaplan–Meier survival analysis of high-risk and low-risk groups in the TCGA set; G: Time-dependent ROC curves analysis of the GILncSig in the TCGA set; H: LncRNA expression patterns, distribution of somatic mutations, UBQLN4 and H2AX expression with increasing GILncSig score in the TCGA set; I: The boxplots of the distribution of somatic mutations, and the expression of UBQLN4, H2AX between the high-risk and low-risk groups in the TCGA group.

Figure 5 Receiver operating characteristic analysis was used to evaluate the performance of the genomic instability-derived long non-coding RNAs signature, genomically unstable-derived long non-coding RNAs signature, and WuLncSig. The area under the curve of overall survival for the genomic instability-derived long non-coding RNAs (LncRNAs) signature, genomically unstable-derived LncRNAs signature and WulncSig was 0.736, 0.664 and 0.725, respectively. GILncSig: Genomic instability-derived long non-coding RNAs signature; GuLncSig: Genomically unstable-derived long non-coding RNAs signature; WuLncSig: LncRNA signature derived from Wu’s study; AUC: Area under the curve.

Figure 6 Kaplan–Meier survival analyses of patients with different clinical characteristics. Kaplan–Meier curve analysis of overall survival in the high-risk and low-risk groups. A: Age older than 65 years and age younger than or equal to 65 years; B: Male and female; C: Grade 1-2 and Grade 3-4; D: Stage I-II and stage III-IV; E: T1-2 and T3-4; F: M0 and M1; G: N0 and N1-3.

Figure 7 Comparison of the genomic instability-derived long non-coding RNA signature with TP53 mutation status for prognosis. A: The proportion of TP53 mutation in the high- and low-risk groups in the training set, testing set and the TCGA set; B: Kaplan-Meier curve analysis of overall survival based on TP53 mutation status and genomic instability-derived long non-coding RNA signature classification. GU: Genomically unstable; GS: Genomically stable.