肺腺癌中功能性增强子RNA的综合表征揭示了新的调节因子和一种预后相关的分子亚型。
Comprehensive characterization of functional eRNAs in lung adenocarcinoma reveals novel regulators and a prognosis-related molecular subtype.
作者信息
Qin Na, Ma Zijian, Wang Cheng, Zhang Erbao, Li Yuancheng, Huang Mingtao, Chen Congcong, Zhang Chang, Fan Jingyi, Gu Yayun, Xu Xianfeng, Yang Liu, Wei Xiaoxia, Yin Rong, Jiang Yue, Dai Juncheng, Jin Guangfu, Xu Lin, Hu Zhibin, Shen Hongbing, Ma Hongxia
机构信息
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.
出版信息
Theranostics. 2020 Sep 14;10(24):11264-11277. doi: 10.7150/thno.47039. eCollection 2020.
As the transcriptional products of active enhancers, enhancer RNAs (eRNAs) are essential for the initiation of tumorigenesis. However, the landscape and functional characteristics of eRNAs in Chinese lung adenocarcinoma, and the clinical utility of eRNA-based molecular subtypes remain largely unknown. A genome-wide profiling of eRNAs was performed in 80 Chinese lung adenocarcinoma patients with RNA-seq data. Functional eRNAs and associated genes were identified between paired adenocarcinoma and adjacent samples. Unsupervised clustering of functional eRNAs was conducted and the associations with molecular characteristics and clinical outcomes were accessed by integrating whole-genome sequencing data and clinical data. Additionally, 481 lung adenocarcinoma patients were used for the validation based on The Cancer Genome Atlas (TCGA) dataset. A total of 3297 eRNAs with sufficient expression were identified, which were globally upregulated in adenocarcinoma samples compared to matched-adjacent pairs ( 7.61×10). Further analyses indicated that these upregulated eRNAs were correlated with copy number amplification (CNA) status (Cor = 0.22, 0.045), and eRNA-correlated genes were primarily involved in cell cycle and immune system-related pathways. Based on the co-expression analysis of eRNAs with protein-coding genes, we defined 188 functional eRNAs and their correlated genes were overrepresented in cancer driver genes (ER = 1.98, 5.95×10) and clinically-actionable genes (ER = 2.19, 3.44×10). The eRNA-based consensus clustering further identified a novel molecular subtype with immune deficiency and a high-level of genomic alterations, which was associated with poor clinical outcomes of lung adenocarcinoma patients (OS: HR = 1.91, 0.015; PFI: HR = 1.64, 0.034). The genome-wide identification and characterization of eRNAs reveal novel regulators for the development of lung cancer, which provides a new biological dimension for the understanding of eRNAs during lung carcinogenesis and emphasize the clinical utility of eRNA-based molecular subtypes in the treatment of lung adenocarcinoma.
作为活性增强子的转录产物,增强子RNA(eRNA)对于肿瘤发生的起始至关重要。然而,中国肺腺癌中eRNA的图谱和功能特征,以及基于eRNA的分子亚型的临床效用仍 largely未知。在80例有RNA测序数据的中国肺腺癌患者中进行了eRNA的全基因组分析。在配对的腺癌和相邻样本之间鉴定出功能性eRNA及其相关基因。对功能性eRNA进行无监督聚类,并通过整合全基因组测序数据和临床数据来评估其与分子特征和临床结局的关联。此外,基于癌症基因组图谱(TCGA)数据集,使用481例肺腺癌患者进行验证。共鉴定出3297个有足够表达的eRNA,与匹配的相邻样本相比,这些eRNA在腺癌样本中整体上调(7.61×10)。进一步分析表明,这些上调的eRNA与拷贝数扩增(CNA)状态相关(Cor = 0.22,0.045),且与eRNA相关的基因主要参与细胞周期和免疫系统相关途径。基于eRNA与蛋白质编码基因的共表达分析,我们定义了188个功能性eRNA,其相关基因在癌症驱动基因(ER = 1.98,5.95×10)和临床可操作基因(ER = 2.19,3.44×10)中过度富集。基于eRNA的一致性聚类进一步鉴定出一种具有免疫缺陷和高水平基因组改变的新型分子亚型,其与肺腺癌患者的不良临床结局相关(总生存期:HR = 1.91,0.015;无进展生存期:HR = 1.64,0.034)。eRNA的全基因组鉴定和表征揭示了肺癌发生发展的新型调节因子,这为理解肺癌发生过程中的eRNA提供了新的生物学维度,并强调了基于eRNA的分子亚型在肺腺癌治疗中的临床效用。