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

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 potent...

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Autores principales: Jianhua Wu, Xueting Ren, Nan Wang, Ruina Zhou, Mengsha Chen, Yifan Cai, Shuai Lin, Hao Zhang, Xin Xie, Chengxue Dang, Shuqun Zhang, Zhangjian Zhou
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Publicado: Frontiers Media S.A. 2021
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spelling oai:doaj.org-article:3a7983a548fe4b899c8a0ab70c7721cb2021-11-22T06:18:49ZA Mutation-Related Long Noncoding RNA Signature of Genome Instability Predicts Immune Infiltration and Hepatocellular Carcinoma Prognosis1664-802110.3389/fgene.2021.779554https://doaj.org/article/3a7983a548fe4b899c8a0ab70c7721cb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.779554/fullhttps://doaj.org/toc/1664-8021Background: 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.Jianhua WuXueting RenNan WangRuina ZhouMengsha ChenYifan CaiShuai LinHao ZhangXin XieChengxue DangShuqun ZhangZhangjian ZhouFrontiers Media S.A.articlegenomic instabilitylong non-coding RNAshepatocellular carcinomaprognosisimmune infiltrationGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution DOAJ
collection DOAJ
language EN
topic genomic instability
long non-coding RNAs
hepatocellular carcinoma
prognosis
immune infiltration
Genetics
QH426-470
spellingShingle genomic instability
long non-coding RNAs
hepatocellular carcinoma
prognosis
immune infiltration
Genetics
QH426-470
Jianhua Wu
Xueting Ren
Nan Wang
Ruina Zhou
Mengsha Chen
Yifan Cai
Shuai Lin
Hao Zhang
Xin Xie
Chengxue Dang
Shuqun Zhang
Zhangjian Zhou
A Mutation-Related Long Noncoding RNA Signature of Genome Instability Predicts Immune Infiltration and Hepatocellular Carcinoma Prognosis
description 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.
format article
author Jianhua Wu
Xueting Ren
Nan Wang
Ruina Zhou
Mengsha Chen
Yifan Cai
Shuai Lin
Hao Zhang
Xin Xie
Chengxue Dang
Shuqun Zhang
Zhangjian Zhou
author_facet Jianhua Wu
Xueting Ren
Nan Wang
Ruina Zhou
Mengsha Chen
Yifan Cai
Shuai Lin
Hao Zhang
Xin Xie
Chengxue Dang
Shuqun Zhang
Zhangjian Zhou
author_sort Jianhua Wu
title A Mutation-Related Long Noncoding RNA Signature of Genome Instability Predicts Immune Infiltration and Hepatocellular Carcinoma Prognosis
title_short A Mutation-Related Long Noncoding RNA Signature of Genome Instability Predicts Immune Infiltration and Hepatocellular Carcinoma Prognosis
title_full A Mutation-Related Long Noncoding RNA Signature of Genome Instability Predicts Immune Infiltration and Hepatocellular Carcinoma Prognosis
title_fullStr A Mutation-Related Long Noncoding RNA Signature of Genome Instability Predicts Immune Infiltration and Hepatocellular Carcinoma Prognosis
title_full_unstemmed A Mutation-Related Long Noncoding RNA Signature of Genome Instability Predicts Immune Infiltration and Hepatocellular Carcinoma Prognosis
title_sort mutation-related long noncoding rna signature of genome instability predicts immune infiltration and hepatocellular carcinoma prognosis
publisher Frontiers Media S.A.
publishDate 2021
url https://doaj.org/article/3a7983a548fe4b899c8a0ab70c7721cb
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