A Mutation-Related Long Noncoding RNA Signature of Genome Instability Predicts Immune Infiltration and Hepatocellular Carcinoma Prognosis

Abstract

Background: Long noncoding RNAs (lncRNAs) have been discovered to play a regulatory role in genomic instability (GI), which participates in the carcinogenesis of various cancers, including hepatocellular carcinoma (HCC). We endeavored to establish a GI-derived lncRNA signature (GILncSig) as a potential biomarker and explore its impact on immune infiltration and prognostic significance.Methods: Combining expression and somatic mutation profiles from The Cancer Genome Atlas database, we identified GI-related lncRNAs and conducted functional analyses on co-expressed genes. Based on Cox regression analysis, a GILncSig was established in the training cohort (n = 187), and an independent testing patient cohort (n = 183) was used to validate its predictive ability. Kaplan-Meier method and receiver operating characteristic curves were adopted to evaluate the performance. The correlation between GI and immune infiltration status was investigated based on the CIBERSORT algorithm and single sample gene set enrichment analysis. In addition, a comprehensive nomogram integrating the GILncSig and clinicopathological variables was constructed to efficiently assess HCC patient prognosis in clinical applications.Results: A total of 88 GI-related lncRNAs were screened out and the functional analyses indicated diversified effects on HCC progression. The GILncSig was established using four independent lncRNAs (AC116351.1, ZFPM2-AS1, AC145343.1, and MIR210HG) with significant prognostic value (p < 0.05). Following evaluation with the GILncSig, low-risk patients had significantly better clinical outcomes than high-risk patients in the training cohort (p < 0.001), which was subsequently validated in the independent testing cohort. High-risk group exhibited more immunocyte infiltration including B cells memory, macrophages M0 and neutrophils and higher expression of HLA gene set and immune checkpoint genes. Compared to existing HCC signatures, the GILncSig showed better prognosis predictive performance [area under the curve (AUC) = 0.709]. Furthermore, an integrated nomogram was constructed and validated to efficiently and reliably evaluate HCC patient prognosis (3-years survival AUC = 0.710 and 5-years survival AUC = 0.707).Conclusion: The GILncSig measuring GI and impacting immune infiltration serves as a potential biomarker and independent predictor of HCC patient prognosis. Our results highlight further investigation of GI and HCC molecular mechanisms.

A novel Cuproptosis-related LncRNA signature to predict prognosis in hepatocellular carcinoma

“…However, their functions and mechanisms of them have not been reported so far in HCC. AC145343.1 can be involved in the regulation of immune cell infiltration as TP53 mutation-associated lncRNA and predict HCC patient prognosis 43 , 44 . High GIHCG expression was linked to a shorter patient survival time and was also an independent predictive factor for overall survival in HCC 45 , which was in line with our findings.…”

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

“…The predictive performance of the GILncSig in our study was then compared with two published LncRNA signatures for predicting HCC prognosis: 6-LncRNA signature derived from Gu’s study (hereinafter referred to as GuLncSig)[ 24 ] and 4-LncRNA signature derived from Wu’s study (hereinafter referred to as WuLncSig)[ 25 ] using the same TCGA patient cohort. On this basis, ROC curve analysis was used to evaluate the prognostic performance of these signatures.…”

“…LUCAT1 has also been found to be directly associated with the development and progression of cancers, including HCC, and its inhibition of ANXA2 phosphorylation in HCC promotes tumorigenesis[ 43 , 44 ]. AC010643.1 and AC116351.1 have been used as key components of the recently published LncRNA signatures for predicting HCC prognosis, suggesting that they have great potential as new prognostic markers[ 25 , 45 , 46 ]. However, little is known about AC016735.1 .…”

“…Many previous studies have used similar methods to find prognosis-related LncRNAs and establish LncRNA signatures to predict the prognosis of HCC, such as the studies by Huang et al [ 49 ] and Wu et al [ 25 ]. Moreover, as all data used in this study were collected from TCGA database, similar results could be obtained when searching for GI-LncRNAs and exploring their functional pathways.…”

A Genomic Instability-Related Long Noncoding RNA Signature for Predicting Hepatocellular Carcinoma Prognosis

“…Study showed that lncRNA is upregulated in colorectal cancer and correlated with poor prognosis [ 22 ]. Wu's research focused on the genomic instability-related lncRNAs in HCC and established a prognosis model consisting of 4 lncRNAs [ 23 ]. However, the relationship and mechanism between genomic instability and lncRNAs in tumor prognosis were largely ignored; therefore, we explored whether GI-related lncRNAs are associated with tumorigenesis and prognosis.…”