Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Cancer is associated with widespread DNA methylation and chromatin changes.
• The impact of these alterations on higher-order chromosomal structure is not well understood.

Purpose of the Study:

• To characterize alterations in chromatin loops, topologically associated domains, and large-scale genome compartments in colon tumors.
• To investigate the functional consequences of these topological changes in cancer progression.

Main Methods:

• Integration of topological maps from colon tumors and normal colons.
• Analysis of epigenetic, transcriptional, and imaging data.
• Comparison of genomic organization in malignant and non-malignant cells.

Main Results:

• Spatial partitioning of open and closed genome compartments is significantly disrupted in tumors.
• Tumor-associated topological changes include compartment-specific hypomethylation and chromatin alterations.
• A novel compartment at the A/B compartment interface is reorganized in tumors, with similar shifts observed in non-malignant cells with excess divisions.

Conclusions:

• Tumor-associated topological genome alterations may repress stemness and invasion programs.
• These changes can induce anti-tumor immunity genes, potentially restraining malignant progression.
• The findings challenge the view that epigenomic alterations in cancer are solely oncogenic.