Leveraging Tissue-Specific Enhancer-Target Gene Regulatory Networks Identifies Enhancer Somatic Mutations That...

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Enhancers are noncoding DNA regions regulating gene transcription, often over long distances.
• Alterations in enhancers are linked to various diseases, including cancer, but identifying functional mutations is challenging.
• Somatic mutations in noncoding regulatory regions are implicated in tumorigenesis and prognosis.

Purpose of the Study:

• To develop a strategy for detecting and characterizing enhancer mutations in lung cancer.
• To analyze the functional impact of these mutations on gene expression and biological pathways.
• To explore the potential of enhancer mutations for patient classification.

Main Methods:

• Genome-wide analysis of patient cohorts across three lung cancer subtypes.
• Definition of lung tissue-specific enhancers using experimental and epigenomic data.
• Construction of enhancer-target gene regulatory networks integrating 3D chromatin architecture.
• Prioritization of functionally relevant mutations based on pathway-level integration and frequency.

Main Results:

• Lung cancers show similar mutation burdens in enhancers and exons, but with distinct mutation signatures.
• Mutated enhancers converge on key biological processes and pathways relevant to tumor biology.
• Recurrent enhancer mutations alter target gene expression, impacting patient prognosis.

Conclusions:

• Noncoding regulatory mutations in enhancers play a significant role in cancer pathogenesis.
• These findings highlight the potential of enhancer mutations for understanding cancer development and for patient classification.