CoRAL Accurately Resolves Extrachromosomal DNA Genome Structures with Long-Read Sequencing

Extrachromosomal DNA (ecDNA) is a central mechanism of focal oncogene amplification in cancer and can drive tumor formation, evolution, and drug resistance. Elucidating the genomic architecture of ecDNA amplifications is critical for understanding tumor pathology and developing more effective therapies. Current short-read based methods can predict the ecDNA presence in cancer samples, but are limited in resolving complex and heterogeneous ecDNA structures. Here, we propose CoRAL, an algorithm for identifying and reconstructing ecDNA amplicon structures from long-reads. CoRAL takes mapped long-reads as input, builds a breakpoint graph for each focally amplified region, and extracts cycles from the breakpoint graph representing the ecDNA structures. Through extensive benchmarks on simulated data and previously-characterized cell lines, we report that CoRAL substantially improves breakpoint detection and reconstruction of complex ecDNA structures over the existing short and long-read based methods. Code Availability: https://github.com/AmpliconSuite/CoRAL .