Leveraging tissue-specific enhancer-target gene regulatory networks identifies enhancer somatic mutations that functionally impact lung cancer.

Enhancers are non-coding regulatory DNA regions that modulate the transcription of target genes, often over large distances along the genomic sequence. Enhancer alterations have been associated with various pathological conditions, including cancer. However, the identification and characterization of somatic mutations in non-coding regulatory regions with a functional effect on tumorigenesis and prognosis remain a major challenge. Here we present a strategy for detecting and characterizing enhancer mutations in a genome-wide analysis of patient cohorts, across three lung cancer subtypes. Lung tissue-specific enhancers were defined by integrating experimental data and public epigenomic profiles, and the genome-wide enhancer-target gene regulatory network of lung cells was constructed by integrating chromatin 3D architecture data. Lung cancers possessed a similar mutation burden at tissue-specific enhancers and exons but with differences in their mutation signatures. Functionally relevant alterations were prioritized based on the pathway-level integration of the effect of a mutation and the frequency of mutations on individual enhancers. The genes enriched for mutated enhancers converged on the regulation of key biological processes and pathways relevant to tumor biology. Recurrent mutations in individual enhancers also impacted the expression of target genes with potential relevance for patient prognosis. Together, these findings show that non-coding regulatory mutations have a potential relevance for cancer pathogenesis and can be exploited for patient classification.