Wei Xiyi, Wang Yichun, Ji Chengjian, Luan Jiaocheng, Yao Liangyu, Zhang Xi, Wang Shuai, Yao Bing, Qin Chao, Song Ninghong
The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Medical Genetics, Nanjing Medical University, Nanjing, China.
Front Genet. 2021 Oct 12;12:706661. doi: 10.3389/fgene.2021.706661. eCollection 2021.
Long non-coding RNAs (lncRNAs) are now under discussion as novel promising biomarkers for clear cell renal cell carcinoma (ccRCC). However, the role of genomic instability-associated lncRNA signatures in tumors has not been thoroughly uncovered. The purpose of our study is to probe the role of genomic instability-derived lncRNA signature (GILncSig) and to further investigate the mechanism of genomic instability-mediated ccRCC progression. The transcriptome data and somatic mutation profiles of ccRCC as well as clinical characteristics used in this study were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database. Lasso regression analysis was performed to construct the GILncSig. Gene set enrichment analysis (GSEA) was performed to elucidate the biological functions and relative pathways. CIBERSORT and EPIC algorithm were applied to calculate the proportion of immune cells in ccRCC. ESTIMATE algorithm was utilized to compute the immune microenvironment scores. In total, 148 novel genomic instability-derived lncRNAs in ccRCC were identified. Immediately, on the basis of univariate cox analysis and lasso analysis, a GILncSig was appraised, through which the patients were allocated into High-Risk and Low-Risk groups with significantly different characteristics and prognoses. In addition, we confirmed that the somatic mutation count, tumor mutation burden, and the expression of UBQLN4, which were ascertainably associated with genomic instability, were significantly correlated with the GILncSig, indicating its reliability as a measurement of the genomic instability. Furthermore, the efficiency of GILncSig in prognostic aspects was better than the single mutation gene in ccRCC. In addition, MNX1-AS1 was defined to be a potential biomarker characterized by strong correlation with clinical features. Moreover, GSEA results indicated that the IL6/JAK/STAT3/SIGNALING pathway could be considered as a potential mechanism of genomic instability to influence tumor progression. Besides, the immune microenvironment showed significant differences between the GS-like group and the GU-like group, which was specifically manifested as high expression of CTLA4, GITR, TNFSF14, and regulatory T cells (Tregs) as well as low expression of endothelial cells (ECs) in the GU-like group. Finally, the prognostic value and clinical relevance of GILncSig were verified in GEO datasets and other urinary tumors in TCGA dataset. In conclusion, our study provided a new perspective for the role of lncRNAs in genomic instability and revealed that genomic instability may mediate tumor progression by affecting immunity. Besides, MNX1-AS1 played critical roles in promoting the progression of ccRCC, which may be a potential therapeutic target. What is more, the immune atlas of genomic instability was characterized by high expression of CTLA4, GITR, TNFSF14, and Tregs, and low expression of ECs.
长链非编码RNA（lncRNAs）目前正作为肾透明细胞癌（ccRCC）新的有前景的生物标志物进行讨论。然而，基因组不稳定相关lncRNA特征在肿瘤中的作用尚未完全阐明。我们研究的目的是探究基因组不稳定衍生的lncRNA特征（GILncSig）的作用，并进一步研究基因组不稳定介导ccRCC进展的机制。本研究中使用的ccRCC转录组数据、体细胞突变谱以及临床特征来自癌症基因组图谱数据库和基因表达综合数据库。进行套索回归分析以构建GILncSig。进行基因集富集分析（GSEA）以阐明生物学功能和相关途径。应用CIBERSORT和EPIC算法计算ccRCC中免疫细胞的比例。利用ESTIMATE算法计算免疫微环境评分。总共在ccRCC中鉴定出148种新的基因组不稳定衍生的lncRNAs。随后，基于单变量cox分析和套索分析，评估了一个GILncSig，通过该特征将患者分为具有显著不同特征和预后的高风险组和低风险组。此外，我们证实与基因组不稳定确定相关的体细胞突变计数、肿瘤突变负担以及UBQLN4的表达与GILncSig显著相关，表明其作为基因组不稳定测量指标的可靠性。此外，GILncSig在ccRCC预后方面的效率优于单个突变基因。此外，MNX1-AS1被定义为一种潜在的生物标志物，其与临床特征具有强相关性。此外，GSEA结果表明IL6/JAK/STAT3/信号通路可被视为基因组不稳定影响肿瘤进展的潜在机制。此外，免疫微环境在GS样组和GU样组之间存在显著差异，具体表现为GU样组中CTLA4、GITR、TNFSF14和调节性T细胞（Tregs）高表达以及内皮细胞（ECs）低表达。最后，在GEO数据集和TCGA数据集中的其他泌尿系统肿瘤中验证了GILncSig的预后价值和临床相关性。总之，我们的研究为lncRNAs在基因组不稳定中的作用提供了新的视角，并揭示基因组不稳定可能通过影响免疫介导肿瘤进展。此外，MNX1-AS1在促进ccRCC进展中起关键作用，可能是一个潜在的治疗靶点。更重要的是，基因组不稳定的免疫图谱特征为CTLA4、GITR、TNFSF14和Tregs高表达以及ECs低表达。
