Enhancer somatic mutations with functional impact in lung cancers identified by leveraging the tissue-specific enhancer-target genes regulatory network [ATAC-seq]. Enhancer somatic mutations with functional impact in lung cancers identified by leveraging the tissue-specific enhancer-target genes regulatory network [ATAC-seq]

Enhancers are non-coding genomic features that regulate the transcriptional output of their target genes. Their dysregulation has been associated with various diseases including cancer. However, identification and characterisation of non-coding mutations that are relevant for tumorigenesis and prognosis remain a major challenge. Here we present the detection and characterisation of enhancer mutations in a genome-wide analysis of three lung cancer subtypes. We carefully define lung tissue-specific enhancers across the genome by integrating novel experimental data and reference public datasets of epigenomic signatures from eight lung cell lines and primary tissue. We observe that in lung cancer, the mutation burden at enhancers and exons is similar, whereas their corresponding mutation signatures show stark differences. Our results indicate that recurrent mutations in individual enhancers significantly impact the expression of target genes with potential relevance for prognosis. We also demonstrate that the genes enriched for mutated enhancers recurrently converge on the regulation of key biological process and pathways. Overall design: Genomewide lung specific enhancer profiling using epigenomic signatures

增强子（enhancer）是一类非编码基因组特征，可调控其靶基因的转录输出。其功能失调与包括癌症在内的多种疾病密切相关。然而，鉴定与肿瘤发生及预后相关的非编码突变仍是领域内的重大挑战。本研究通过对三种肺癌亚型开展全基因组分析，完成了增强子突变的检测与特征解析工作。我们通过整合全新实验数据与来自8种肺细胞系及原代组织的表观基因组特征公共参考数据集，在全基因组范围内精准界定了肺组织特异性增强子。研究观察到，肺癌中增强子区域与外显子区域的突变负荷水平相近，但二者对应的突变特征却呈现出显著差异。我们的研究结果表明，单个增强子上的复发性突变可显著影响靶基因的表达，且该现象与预后存在潜在关联。我们还证实，携带复发性突变增强子的富集基因，会反复汇聚于关键生物学过程及通路的调控网络之中。整体实验设计：基于表观基因组特征开展全基因组肺特异性增强子谱分析。