A Distinct Mode of Chromosome-End Genome Instability Revealed by Circulome Characterization and Analyses

Genome instability is a hallmark of cancer, characterized by mutations, copy-number changes, and rearrangements compared to a linear reference. However, DNA also has physical forms, such as circular DNA (eccDNA), which can arise from specific regions in chromosomes. EccDNA can participate in phenotypic selection and provide insight into the genomic instability landscape.

Traditionally, genome maps of eccDNA have not been available at scale or high resolution. To create such maps, physical selection of circular species is necessary, as most sequenced reads from unselected DNA come from unrearranged sequence, blending the signal from dynamic rearrangements with that from bulk chromosomal DNA.

In this study, researchers combined biophysical and biochemical isolation of circular DNA with next-generation sequencing to analyze a variety of samples, including cancer cell lines, patient tumors, non-cancerous cells, and adjacent normal tissues. The resulting genome-wide maps, dubbed the Circulome, showed a consistent enrichment of eccDNA at the ends of chromosomes, extending well past the telomeres up to tens of megabases inward.

This activity, along with corroborating rearrangements in the linear genome, defines a localized mode of instability in cancer, termed Erosion at Distal Genomic Ends (EDGE).

To differentiate bladder tumor from matched normal tissue, the researchers developed a classification problem and found that the EDGE signal outperforms the mean of all interior chromosomal regions on each chromosome. These findings reveal a unique spatial signature of cancer chromosome instability that can be detected through Circulome analysis, connecting early models of region-specific instability to the human cancer genome.