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