A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers

Area of Science:

• Genomics
• Cancer Biology
• Bioinformatics

Background:

• Somatic mutations are key drivers of cancer development.
• Regulatory mutations, though less studied than coding mutations, are increasingly recognized in cancer.
• Transcription factors (TFs) play crucial roles in gene regulation and cancer.

Purpose of the Study:

• To develop a new strategy for identifying putative regulatory mutations.
• To investigate the impact of these mutations on transcription factor binding affinity.
• To explore the association of identified regulatory mutations with cancer-related genes and pathways.

Main Methods:

• Utilizing experimentally established transcription factor (TF) binding motifs.
• Developing a computational strategy to predict regulatory mutations impacting TF binding affinity.
• Analyzing mutation data in hepatocellular carcinoma, esophagus, gastric, and pancreatic cancers.
• Assessing the enrichment of cancer-related genes near mutated motifs.

Main Results:

• Identified 1,552 candidate regulatory mutations predicted to reduce TF binding affinity.
• Found mutations affecting TF binding in hepatocellular carcinoma.
• Observed CTCF binding disruption by mutations in esophagus, gastric, and pancreatic cancers.
• Demonstrated significant enrichment of cancer-associated genes, tumor suppressors, and KEGG cancer pathway genes near mutated motifs.

Conclusions:

• The developed strategy effectively identifies potential regulatory mutations driving cancer.
• These findings highlight the importance of regulatory regions in cancer etiology.
• The approach is broadly applicable for discovering cancer-contributing genes across various cancer types.