Circlehunter: a tool to identify extrachromosomal circular DNA from ATAC-Seq data

In cancer, extrachromosomal circular DNA (ecDNA), or megabase-pair amplified circular DNA, plays an essential role in intercellular heterogeneity and tumor cell revolution because of its non-Mendelian inheritance. We developed circlehunter (https://github.com/ suda-huanglab/circlehunter), a tool for identifying ecDNA from ATAC-Seq data using the enhanced chromatin accessibility of ecDNA. Using simulated data, we showed that circlehunter has an F1 score of 0.93 at 30x local depth and read lengths as short as 35 bp. Based on 1312 ecDNAs predicted from 94 publicly available datasets of ATAC-Seq assays, we found 37 oncogenes contained in these ecDNAs with amplification characteristics. In small cell lung cancer cell lines, ecDNA containing MYC leads to amplification of MYC and cis-regulates the expression of NEUROD1, resulting in an expression pattern consistent with the NEUROD1 high expression subtype and sensitive to Aurora kinase inhibitors. This showcases that circlehunter could serve as a valuable pipeline for the investigation of tumorigenesis.

Automated summary

In cancer, ecDNA plays a crucial role in intercellular heterogeneity and tumor cell evolution due to its non-Mendelian inheritance. We developed circlehunter, a tool that uses enhanced chromatin accessibility to identify ecDNA from ATAC-Seq data. Circlehunter has an F1 score of 0.93 at 30x local depth and read lengths as short as 35 bp based on simulated data. Analysis of publicly available ATAC-Seq datasets revealed 37 oncogenes contained in ecDNA with amplification characteristics. Additionally, we found that ecDNA containing MYC in small cell lung cancer cell lines leads to MYC amplification and cis-regulation of NEUROD1 expression, resulting in a phenotype consistent with the NEUROD1 high expression subtype and sensitivity to Aurora kinase inhibitors. These findings highlight the value of circlehunter as a pipeline for investigating tumorigenesis.